Epinephrine spray formulations

ABSTRACT

Provided herein are epinephrine spray formulations. Also provided herein are methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatment.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/644,834, filed Mar. 19, 2018, U.S. Provisional Application No.62/663,100, filed Apr. 26, 2018, U.S. Provisional Application No.62/712,678, filed Jul. 31, 2018, U.S. Provisional Application No.62/747,048, filed Oct. 17, 2018, and U.S. Provisional Application No.62/810,261, filed Feb. 25, 2019, which applications are incorporatedherein in their entirety by reference.

BACKGROUND OF THE INVENTION

Epinephrine is a catecholamine that stimulates the α- and β-adrenergicreceptors of the sympathetic nervous system. Epinephrine binds to theseadrenergic receptors leading to relief of many life-threatening symptomsof anaphylaxis (e.g., relaxation of the smooth muscle in the bronchi ofthe lungs thereby opening up constricted airways, constriction of theblood vessels leading to decreased swelling of the tongue and throat andincreasing blood pressure, and increased heart rate thereby preventingor reversing cardiovascular collapse).

BRIEF SUMMARY OF THE INVENTION

In an aspect provided herein, is a pharmaceutical spray formulation. Insome embodiments, the pharmaceutical spray formulation includes fromabout 0.5% to about 25% w/w of epinephrine, or a pharmaceuticallyacceptable salt of epinephrine, in water, wherein the pH of theformulation is from about 4.0 to about 6.5. In some embodiments, thepharmaceutical spray formulation includes from about 0.5% to about 25%w/w of epinephrine, or a pharmaceutically acceptable salt ofepinephrine, in water, ethanol, propylene glycol, or a combinationthereof. In some embodiments, the pharmaceutical spray formulationincludes from about 0.5% to about 25% w/w of epinephrine, or apharmaceutically acceptable salt of epinephrine, in water, ethanol,propylene glycol, or a combination thereof. In some embodiments, thepharmaceutical spray formulation includes from about 0.5% to about 10%w/w of epinephrine, or a pharmaceutically acceptable salt ofepinephrine, in water, ethanol, propylene glycol, or a combinationthereof. In some embodiments, the pH of the pharmaceutical sprayformulation is from about 4.0 to about 6.5.

In one aspect, disclosed herein is a pharmaceutical spray formulationcomprising from about 0.5% to about 25% w/w of epinephrine, or apharmaceutically acceptable salt of epinephrine, in water, wherein thepH of the formulation is from about 4.0 to about 6.5. In someembodiments, the pharmaceutical spray formulation comprises from about0.5% to about 10% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the pharmaceutical spray formulationcomprises from about 2% to about 5% w/w of epinephrine. In someembodiments, the pharmaceutical spray formulation comprises about 2% w/wof epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises about 5% w/w of epinephrine. In some embodiments,the pharmaceutical spray formulation further comprises one or more of anantioxidant, an antimicrobial preservative, an isotonicity agent, anabsorption enhancer, a viscosity modifier, or a buffering agent. In someembodiments, the pharmaceutical spray formulation comprises anantioxidant, an antimicrobial preservative, an isotonicity agent, anabsorption enhancer, a viscosity modifier, and a buffering agent. Insome embodiments, the pharmaceutical spray formulation comprises anantioxidant. In some embodiments, the pharmaceutical spray formulationcomprises the antioxidant comprises sodium bisulfite or sodiummetabisulfite. In some embodiments, the pharmaceutical spray formulationcomprises the antioxidant at a concentration from about 0.0001% (w/w) toabout 0.1% (w/w). In some embodiments, the pharmaceutical sprayformulation comprises the antioxidant at a concentration from about0.001% (w/w) to about 0.1% (w/w). In some embodiments, thepharmaceutical spray formulation comprises the antioxidant at aconcentration from about 0.01% (w/w) to about 0.1% (w/w). In someembodiments, the pharmaceutical spray formulation comprises theantioxidant at a concentration of about 0.05% (w/w). In someembodiments, the pharmaceutical spray formulation comprises anantimicrobial preservative. In some embodiments, the pharmaceuticalspray formulation comprises the antimicrobial preservative compriseschlorobutanol. In some embodiments, the pharmaceutical spray formulationcomprises the antimicrobial preservative at a concentration from about0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceuticalspray formulation comprises the antimicrobial preservative at aconcentration from about 0.01% (w/v) to about 1% (w/v). In someembodiments, the pharmaceutical spray formulation comprises theantimicrobial preservative at a concentration from about 0.1% (w/v) toabout 1% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises the antimicrobial preservative at a concentrationof about 0.21% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises an isotonicity agent. In some embodiments, thepharmaceutical spray formulation comprises an isotonicity agentcomprises sodium chloride. In some embodiments, the pharmaceutical sprayformulation comprises an isotonicity agent at a concentration from about0.1% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises an isotonicity agent at a concentration from about0.1% to about 1%. In some embodiments, the pharmaceutical sprayformulation comprises an isotonicity agent at a concentration of about0.4%. In some embodiments, the pharmaceutical spray formulationcomprises an absorption enhancer. In some embodiments, thepharmaceutical spray formulation comprises the absorption enhancercomprises diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises the absorption enhancer at aconcentration from about 0.05% to about 15%. In some embodiments, thepharmaceutical spray formulation comprises the absorption enhancer at aconcentration from about 0.1% to about 5%. In some embodiments, thepharmaceutical spray formulation comprises the absorption enhancer at aconcentration of about 1%. In some embodiments, the pharmaceutical sprayformulation comprises a viscosity modifier. In some embodiments, thepharmaceutical spray formulation comprises the viscosity modifiercomprises hypromellose. In some embodiments, the pharmaceutical sprayformulation comprises the viscosity modifier at a concentration fromabout 0.001% to about 0.5%. In some embodiments, the pharmaceuticalspray formulation comprises the viscosity modifier at a concentrationfrom about 0.01% to about 0.2%. In some embodiments, the pharmaceuticalspray formulation comprises the viscosity modifier at a concentration ofabout 0.1%. In some embodiments, the pharmaceutical spray formulationcomprises a buffering agent. In some embodiments, the pharmaceuticalspray formulation comprises the buffering agent comprises citric acid orcitric acid monohydrate. In some embodiments, the pharmaceutical sprayformulation comprises the buffering agent at a concentration from about0.01% to about 2%. In some embodiments, the pharmaceutical sprayformulation comprises the buffering agent at a concentration from about0.1% to about 1%. In some embodiments, the pharmaceutical sprayformulation comprises the buffering agent at a concentration of about0.42%. In some embodiments, the pharmaceutical spray formulationcomprises sodium metabisulfite, sodium chloride, hypromellose, citricacid monohydrate, and diethylene glycol monoethyl ether. In someembodiments, the pharmaceutical spray formulation comprises from about1% to about 20% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 5% sodium chloride, from about0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citricacid monohydrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether. In some embodiments, the pharmaceutical sprayformulation comprises from about 1% to about 20% w/w of epinephrine, ora pharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 2% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 2% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 2% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) ofsodium metabisulfite, about 0.4% sodium chloride, about 0.1%hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 5% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 5% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 5% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) ofsodium metabisulfite, about 0.4% sodium chloride, about 0.1%hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 10% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 10% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 10% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) ofsodium metabisulfite, about 0.4% sodium chloride, about 0.1%hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 20% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 20% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 20% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) ofsodium metabisulfite, about 0.4% sodium chloride, about 0.1%hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises chlorobutanol at aconcentration of from about 0.005% (w/v) to about 10% (w/v). In someembodiments, the pharmaceutical spray formulation compriseschlorobutanol at a concentration of from about 0.01% (w/v) to about 10%(w/v). In some embodiments, the pharmaceutical spray formulationcomprises chlorobutanol at a concentration of from about 0.1% (w/v) toabout 1% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises chlorobutanol at a concentration about 0.21%(w/v). In another aspect, disclosed herein is a spray, comprisingdroplets, wherein the droplets comprise a pharmaceutical sprayformulation described herein. In another aspect, disclosed herein is amethod of treating anaphylaxis, anaphylactic shock, a severe allergicreaction, and/or bronchial constriction, comprising delivering a sprayof a pharmaceutical solution from a pre-primed device into a nostril ofa subject in need thereof, wherein: the device is adapted for nasaldelivery; a volume of from about 20 μL to about 250 μL of spray isdelivered; and the pharmaceutical solution comprises a pharmaceuticalspray formulation described herein. In another aspect, disclosed hereinis a method of treating anaphylaxis- or anaphylactic shock-inducedrespiratory depression or distress, comprising delivering a spray of apharmaceutical solution from a pre-primed device into a nostril of asubject in need thereof in a manner that delivers the pharmaceuticalsolution in a round spray plume with an ovality ratio less than about2.0 when measured at a distance of from about 1 to about 10 cm from thepre-primed device, wherein: the device is adapted for nasal delivery; avolume of from about 20 μL to about 250 μL of spray is delivered; andthe pharmaceutical solution comprises a pharmaceutical spray formulationdescribed herein. In another aspect, disclosed herein is a method fortreating at least one symptom of anaphylaxis or anaphylactic shock,comprising delivering a spray of a pharmaceutical solution from a deviceinto a nostril of a subject in need thereof, wherein: the device isadapted for nasal delivery; a volume of from about 20 μL to about 250 μLof spray is delivered; and the pharmaceutical solution comprises apharmaceutical spray formulation described herein. In some embodiments,a therapeutic plasma concentration of epinephrine in the subject isachieved in less than 20 minutes following administration to thesubject. In some embodiments, the therapeutic plasma concentration ofepinephrine in the subject is about 0.5 ng/mL of epinephrine. In someembodiments, the subject has a maximum plasma concentration (C_(max)) offrom about 0.1 ng/mL to about 1 ng/mL of epinephrine. In someembodiments, the area under a plasma concentration-time curve ofepinephrine in the subject is from about 0.1 ng·h/mL to about 5 ng·h/mL.In some embodiments, the plasma concentration versus time curve ofepinephrine in the subject has a t_(max) of less than from about 10minutes to about 120 minutes. In some embodiments, the device is asingle-dose device. In some embodiments, the device is a bi-dose device.In some embodiments, the device delivers two sprays of thepharmaceutical solution from a single reservoir. In some embodiments,the device has a first reservoir containing from about 50 μL to about250 μL of the pharmaceutical solution and a second reservoir containingfrom about 50 μL to about 250 μL of the pharmaceutical solution. In someembodiments, less than about 20% of the formulation leaves the nasalcavity via drainage into the nasopharynx or externally. In someembodiments, a single spray in a nostril of the subject yields a plasmaconcentration of at least 0.2 ng/mL within 2 minutes in the subject. Inanother aspect, disclosed herein is a stable pharmaceutical sprayformulation, comprising: from about 1% to about 25% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, in water; and one or moreexcipients, vehicles, emulsifiers, stabilizing agents, preservatives,mucosal adhesives, antibacterial agents, buffers, and/or otheradditives, wherein the formulation is stable at a temperature of atleast about 20° C. and at a relative humidity of at least about 30%, andwherein the formulation is stable for a period of at least about twomonths, wherein the stable pharmaceutical formulation is apharmaceutical spray formulation disclosed herein.

In an aspect provided herein, is a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical spray formulationdescribed herein. In some embodiments, the subject is an adult. In someembodiments, the subject is a child. In some embodiments, the childweighs from about 10 lbs to about 80 lbs.

In an aspect provided herein, is a spray including droplets. In thespray, the droplets include in aggregate from about 0.5 mg to about 100mg of epinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and benzalkonium chloride or chlorobutanol. In someembodiments, the spray contains from about 0.005% to about 10% (w/v) ofbenzalkonium chloride or from about 0.005% to about 10% (w/v)chlorobutanol. In some embodiments provided herein, is a spray,comprising droplets, wherein the droplets comprise in aggregate fromabout 0.5 mg to about 100 mg of epinephrine, or a pharmaceuticallyacceptable salt thereof, an isotonicity agent, and from about 0.005%(w/v) to about 10% (w/v) of benzalkonium chloride or from about 0.005%(w/v) to about 10% (w/v) chlorobutanol. In some embodiments, the sprayis delivered from a device. In some embodiments, the device is asingle-dose device. In some embodiments, the device is a bi-dose device.In some embodiments, the device has a single reservoir containing fromabout 125 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the spray is deliveredfrom a device, wherein the device is pre-primed. In some embodiments,the isotonicity agent is present in a concentration from about 0.1%(w/v) to about 5% (w/v). In some embodiments, the isotonicity agent issodium chloride. In some embodiments, the spray takes the shape of around plume with an ovality ratio less than about 2.0. In someembodiments, the spray takes the shape of a round plume with an ovalityratio less than about 1.5. In some embodiments, the spray takes theshape of a round plume with an ovality ratio less than about 1.3. Insome embodiments, the spray takes the shape of a round plume with anovality ratio less than about 1.2. In some embodiments, the spray takesthe shape of a round plume with an ovality ratio less than about 1.1. Insome embodiments, the ovality ratio is measured at a distance of fromabout 1 cm to about 10 cm from the device. In some embodiments, theovality ratio is measured at a distance of from about 1 cm to about 5 cmfrom the device. In some embodiments, the ovality ratio is measured at adistance of about 3 cm from the device. In some embodiments, theepinephrine is at least 10% bioavailable. In some embodiments, theepinephrine is at least 40% bioavailable. In some embodiments, theepinephrine is at least 50% bioavailable. In some embodiments, theepinephrine is at least 60% bioavailable. In some embodiments, themedian droplet size is from about 10 μm to about 120 μm. In someembodiments, no more than about 10% of the droplets have a diameter lessthan about 10 μm. In some embodiments, no more than approximately 5% ofthe droplets have a diameter less than about 10 In some embodiments, nomore than approximately 2% of the droplets have a diameter less thanabout 10 In some embodiments, approximately 50% of the droplets have adiameter of from about 10 μm to about 120 μm. In some embodiments,approximately 50% of the droplets have a diameter of from about 10 μm toabout 60 μm. In some embodiments, approximately 90% of the droplets havea diameter less than about 120 μm. In some embodiments, the sprayfurther comprises a stabilizing agent and an acid. In some embodiments,the spray further comprises a stabilizing agent and an acid, wherein thestabilizing agent is disodium edetate. In some embodiments, the sprayfurther comprises a stabilizing agent and an acid. In some embodiments,the spray further comprises a stabilizing agent and an acid, wherein theacid is hydrochloric acid or citric acid, or a combination thereof. Insome embodiments, the epinephrine, or a pharmaceutically acceptable saltthereof, is dissolved in water, ethanol, or propylene glycol, or acombination thereof. In some embodiments, the spray further comprisessodium bisulfite at a concentration of from about 0.0001% (w/w) to about0.1% (w/w) or sodium metabisulfite at a concentration of from about0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the sprayfurther comprises sodium bisulfite at a concentration of from about0.0001% (w/w) to about 0.05% (w/w) or sodium metabisulfite at aconcentration of from about 0.0001% (w/w) to about 0.05% (w/w). In someembodiments, the spray further comprises sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.1% (w/w). In some embodiments, the spray further comprises sodiumbisulfite at a concentration of from about 0.01% (w/w) to about 0.1%(w/w) or sodium metabisulfite at a concentration of from about 0.01%(w/w) to about 0.1% (w/w). In some embodiments, the spray furthercomprises chlorobutanol at a concentration of from about 0.005% (w/w) toabout 1% (w/w). In some embodiments, the spray further comprises avasodilator. In some embodiments, the spray further comprises avasodilator, wherein the vasodilator is nitroprusside, phentolamine, ornifedipine. In some embodiments, the spray further comprises apermeability enhancer. In some embodiments, the spray further comprisesa permeability enhancer, wherein the permeability enhancer is diethyleneglycol monoethyl ether. In some embodiments, the spray further comprisesa viscosity modifier. In some embodiments, the spray further comprises apermeability enhancer, wherein the viscosity modifier is polyethyleneglycol, methylcellulose, or hypromellose. In some embodiments, the sprayfurther comprises trisodium citrate or citric acid monohydrate. In someembodiments, the spray is delivered from a device, wherein the devicecomprises at least one oxygen absorber or scavenger. In someembodiments, the spray is delivered from a device, wherein the devicecomprises at least one oxygen absorber or scavenger, and wherein the atleast one oxygen absorber or scavenger is iron, ferrous carbonate,ascorbate, or sodium bicarbonate, or a combination thereof. In someembodiments, the spray comprises per 100 μL of solution: from about 0.5mg to about 100 mg of epinephrine, or a pharmaceutically acceptable saltthereof; from about 0.1 mg to about 2 mg sodium chloride; from about0.01 mg to about 1 mg benzalkonium chloride; from about 0.1 mg to about2 mg disodium edetate; and hydrochloric acid or citric acid, or acombination thereof sufficient to achieve a pH of from about 3.5 toabout 6.5. In some embodiments, the spray is delivered from a spraynozzle of a pre-primed device, and wherein no more than about 10% of thedroplets have a diameter less than 10 μm. In some embodiments, the sprayis measured by laser diffraction with beams measuring at both 3 cm and 6cm from the spray nozzle.

In another aspect provided herein, is a stable pharmaceutical sprayformulation where the pharmaceutical spray formulation is stable for aperiod of at least about two months at a temperature of at least about20° C. and at a relative humidity of at least about 30%. The stablepharmaceutical spray formulation includes:

-   -   (i) from about 1% to about 25% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof, in water, ethanol,        propylene glycol, or a combination thereof; and    -   (ii) one or more excipients, vehicles, emulsifiers, stabilizing        agents, preservatives, mucosal adhesives, antibacterial agents,        buffers, and/or other additives, wherein the formulation is        stable at a temperature of at least about 20° C. and at a        relative humidity of at least about 30%, and wherein the        formulation is stable for a period of at least about two months.        In some embodiments, the pharmaceutical spray formulation        comprises from about 1% to about 10% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof. In some embodiments,        the pharmaceutical spray formulation is stable at a temperature        of at least about 25° C. In some embodiments, the pharmaceutical        spray formulation is stable at a temperature of at least about        30° C. In some embodiments, the pharmaceutical spray formulation        is stable at a temperature of at least about 35° C. In some        embodiments, the pharmaceutical spray formulation is stable at a        temperature of at least about 40° C. In some embodiments, the        pharmaceutical spray formulation is stable at a temperature of        at least about 45° C. In some embodiments, the pharmaceutical        spray formulation is stable at a relative humidity of at least        about 40%. In some embodiments, the pharmaceutical spray        formulation is stable at a relative humidity of at least about        50%. In some embodiments, the pharmaceutical spray formulation        is stable at a relative humidity of at least about 60%. In some        embodiments, the pharmaceutical spray formulation is stable at a        relative humidity of at least about 70%. In some embodiments,        the pharmaceutical spray formulation is stable at a relative        humidity of at least about 80%. In some embodiments, the        pharmaceutical spray formulation is stable for a period of at        least about six months. In some embodiments, the pharmaceutical        spray formulation is stable for a period of at least about 12        months. In some embodiments, the pharmaceutical spray        formulation is stable for a period of at least about 18 months.        In some embodiments, the pharmaceutical spray formulation is        stable for a period of at least about 24 months. In some        embodiments, the pharmaceutical spray formulation is stable for        a period of at least about 36 months. In some embodiments, the        pharmaceutical spray formulation has a viscosity of from about        100 to about 2,500 cP. In some embodiments, the pharmaceutical        spray formulation is adapted for parenteral dosing. In some        embodiments, the pharmaceutical spray formulation is adapted for        dosing by inhalation. In some embodiments, the pharmaceutical        spray formulation is adapted for intranasal dosing. In some        embodiments, the pharmaceutical spray formulation further        comprises an isotonicity agent present in a concentration from        about 0.1% (w/w) to about 5% (w/w). In some embodiments, the        pharmaceutical spray formulation further comprises an        isotonicity agent present in a concentration from about 0.1%        (w/w) to about 5% (w/w), wherein the isotonicity agent is sodium        chloride. In some embodiments, the pharmaceutical spray        formulation comprises a stabilizing agent. In some embodiments,        the pharmaceutical spray formulation comprises a stabilizing        agent, wherein the stabilizing agent is disodium edetate. In        some embodiments, the pharmaceutical spray formulation further        comprises an acid sufficient to achieve a pH of from about 3.5        to about 6.5. In some embodiments, the pharmaceutical spray        formulation further comprises an acid sufficient to achieve a pH        of from about 3.5 to about 6.5, wherein the acid is hydrochloric        acid or citric acid, or a combination thereof. In some        embodiments, the spray further comprises sodium bisulfite at a        concentration of from about 0.0001% (w/w) to about 0.1% (w/w) or        sodium metabisulfite at a concentration of from about 0.0001%        (w/w) to about 0.1% (w/w). In some embodiments, the        pharmaceutical spray formulation further comprises sodium        bisulfite at a concentration of from about 0.0001% (w/w) to        about 0.05% (w/w) or sodium metabisulfite at a concentration of        from about 0.0001% (w/w) to about 0.05% (w/w). In some        embodiments, the spray further comprises sodium bisulfite at a        concentration of from about 0.0001% (w/w) to about 0.1% (w/w) or        sodium metabisulfite at a concentration of from about 0.0001%        (w/w) to about 0.1% (w/w). In some embodiments, the spray        further comprises sodium bisulfite at a concentration of from        about 0.01% (w/w) to about 0.1% (w/w) or sodium metabisulfite at        a concentration of from about 0.01% (w/w) to about 0.1% (w/w).        In some embodiments, the pharmaceutical spray formulation        further comprises chlorobutanol at a concentration of from about        0.005% (w/v) to about 1% (w/v). In some embodiments, the        pharmaceutical spray formulation further comprises a        vasodilator. In some embodiments, the pharmaceutical spray        formulation further comprises a vasodilator, wherein the        vasodilator is nitroprusside, phentolamine, or nifedipine. In        some embodiments, the pharmaceutical spray formulation further        comprises a permeability enhancer. In some embodiments, the        pharmaceutical spray formulation further comprises a        permeability enhancer, wherein the permeability enhancer is        diethylene glycol monoethyl ether. In some embodiments, the        pharmaceutical spray formulation further comprises a viscosity        modifier. In some embodiments, the pharmaceutical spray        formulation further comprises a viscosity modifier, wherein the        viscosity modifier is polyethylene glycol, methylcellulose, or        hypromellose. In some embodiments, the pharmaceutical spray        formulation further comprises trisodium citrate or citric acid        monohydrate. In some embodiments, the pharmaceutical spray        formulation comprises from about 1% to about 20% w/w of        epinephrine, or a pharmaceutically acceptable salt thereof, from        about 0.0001% (w/w) to about 0.05% (w/w) of sodium        metabisulfite, from about 0.1% to about 5% sodium chloride, from        about 0.001% to about 0.5% hypromellose, from about 0.01% to        about 2.0% trisodium citrate, and from about 0.05% to about 15%        diethylene glycol monoethyl ether. In some embodiments, the        pharmaceutical spray formulation comprises from about 1% to        about 5% w/w of epinephrine, or a pharmaceutically acceptable        salt thereof, from about 0.01% (w/w) to about 0.05% (w/w) of        sodium metabisulfite, from about 0.1% to about 1.0% sodium        chloride, from about 0.01% to about 0.2% hypromellose, from        about 0.1% to about 1.0% trisodium citrate, and from about 0.1%        to about 2.0% diethylene glycol monoethyl ether. In some        embodiments, the pharmaceutical spray formulation comprises from        about 5% to about 20% w/w of epinephrine, or a pharmaceutically        acceptable salt thereof, from about 0.01% (w/w) to about 0.05%        (w/w) of sodium metabisulfite, from about 0.1% to about 1.0%        sodium chloride, from about 0.05% to about 0.5% hypromellose,        from about 0.1% to about 1.0% trisodium citrate, and from about        0.5% to about 5% diethylene glycol monoethyl ether. In some        embodiments, the pharmaceutical spray formulation comprises        about 2.4% w/w of epinephrine, or a pharmaceutically acceptable        salt thereof, about 0.05% (w/w) of sodium metabisulfite, about        0.4% sodium chloride, about 0.1% hypromellose, about 0.7%        trisodium citrate, and about 1% diethylene glycol monoethyl        ether. In some embodiments, the pharmaceutical spray formulation        comprises about 5% w/w of epinephrine, or a pharmaceutically        acceptable salt thereof, about 0.05% (w/w) of sodium        metabisulfite, about 0.4% sodium chloride, about 0.1%        hypromellose, about 0.7% trisodium citrate, and about 1%        diethylene glycol monoethyl ether. In some embodiments, the        pharmaceutical spray formulation comprises about 10% w/w of        epinephrine, or a pharmaceutically acceptable salt thereof,        about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodium        chloride, about 0.1% hypromellose, about 0.7% trisodium citrate,        and about 1% diethylene glycol monoethyl ether. In some        embodiments, the pharmaceutical spray formulation comprises        about 20% w/w of epinephrine, or a pharmaceutically acceptable        salt thereof, about 0.05% (w/w) of sodium metabisulfite, about        0.4% sodium chloride, about 0.1% hypromellose, about 0.7%        trisodium citrate, and about 1% diethylene glycol monoethyl        ether. In some embodiments, the pharmaceutical spray formulation        comprises from about 1% to about 20% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof, from about 0.0001%        (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about        0.1% to about 5% sodium chloride, from about 0.001% to about        0.5% hypromellose, from about 0.01% to about 2.0% citric acid        monohydrate, and from about 0.05% to about 15% diethylene glycol        monoethyl ether. In some embodiments, the pharmaceutical spray        formulation comprises about 2% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof, about 0.05% (w/w) of        sodium metabisulfite, about 0.4% sodium chloride, about 0.1%        hypromellose, about 0.42% citric acid monohydrate, and about 1%        diethylene glycol monoethyl ether. In some embodiments, the        pharmaceutical spray formulation comprises about 5% w/w of        epinephrine, or a pharmaceutically acceptable salt thereof,        about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodium        chloride, about 0.1% hypromellose, about 0.42% citric acid        monohydrate, and about 1% diethylene glycol monoethyl ether. In        some embodiments, the pharmaceutical spray formulation further        comprises chlorobutanol at a concentration of from about 0.05%        (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical        spray formulation is delivered from a device. In some        embodiments, the device is a single-dose device. In some        embodiments, the device is a bi-dose device. In some        embodiments, the device has a single reservoir containing from        about 125 μL to about 250 μL of the pharmaceutical formulation.        In some embodiments, the device delivers two sprays of the        pharmaceutical solution from a single reservoir. In some        embodiments, the bi-dose device has a first reservoir containing        from about 50 μL to about 250 μL of the pharmaceutical        formulation and a second reservoir containing from about 50 μL        to about 250 μL of the pharmaceutical formulation. In some        embodiments, the device delivers one spray of the pharmaceutical        solution from the first reservoir and one spray of the        pharmaceutical solution from the second reservoir. In some        embodiments, the pharmaceutical spray formulation is delivered        from a device, wherein the device is pre-primed. In some        embodiments, the pharmaceutical spray formulation is delivered        from a device, wherein the device is suitable for delivering the        formulation into the nostril of a subject. In some embodiments,        the pharmaceutical spray formulation is delivered from a device,        wherein the device comprises at least one oxygen absorber or        scavenger. In some embodiments, the pharmaceutical spray        formulation is delivered from a device, wherein the device        comprises at least one oxygen absorber or scavenger, and wherein        the at least one oxygen absorber or scavenger is iron, ferrous        carbonate, ascorbate, or sodium bicarbonate, or a combination        thereof. In some embodiments, the pharmaceutical spray        formulation is delivered as a spray. In some embodiments, the        spray takes the shape of a round plume with an ovality ratio        less than about 2.0. In some embodiments, the spray takes the        shape of a round plume with an ovality ratio less than about        1.5. In some embodiments, the spray takes the shape of a round        plume with an ovality ratio less than about 1.3. In some        embodiments, the spray takes the shape of a round plume with an        ovality ratio less than about 1.2. In some embodiments, the        spray takes the shape of a round plume with an ovality ratio        less than about 1.1. In some embodiments, the ovality ratio is        measured at a distance of from about 1 cm to about 10 cm from        the device. In some embodiments, the ovality ratio is measured        at a distance of from about 1 cm to about 5 cm from the device.        In some embodiments, the ovality ratio is measured at a distance        of about 3 cm from the device. In some embodiments, the        epinephrine is at least 10% bioavailable. In some embodiments,        the epinephrine is at least 40% bioavailable. In some        embodiments, the epinephrine is at least 50% bioavailable. In        some embodiments, the epinephrine is at least 60% bioavailable.        In some embodiments, the median droplet size is from about 10 μm        to about 120 μm. In some embodiments, no more than about 10% of        the droplets have a diameter less than about 10 μm. In some        embodiments, no more than approximately 5% of the droplets have        a diameter less than about 10 μm. In some embodiments, no more        than approximately 2% of the droplets have a diameter less than        about 10 μm. In some embodiments, approximately 50% of the        droplets have a diameter of from about 10 μm to about 120 μm. In        some embodiments, approximately 50% of the droplets have a        diameter of from about 10 μm to about 60 μm. In some        embodiments, approximately 90% of the droplets have a diameter        less than about 120 μm.

Provided herein is a method of treating anaphylaxis, anaphylactic shock,a severe allergic reaction, and/or bronchial constriction. The methodincludes delivering a spray of a pharmaceutical solution from deviceinto a nostril of a subject in need thereof where:

-   -   (i) the device is adapted for nasal delivery;    -   (ii) a volume of from about 20 μL to about 250 μL of spray is        delivered; and    -   (iii) the pharmaceutical solution comprises from about 0.5 mg to        about 100 mg of epinephrine, or a pharmaceutically acceptable        salt thereof, an isotonicity agent, and from about 0.005% (w/v)        to about 1% (w/v) of benzalkonium chloride. In some embodiments,        the device is a single-dose device. In some embodiments, the        device is a bi-dose device. In some embodiments, the device has        a single reservoir containing from about 125 μL to about 250 μL        of the pharmaceutical formulation. In some embodiments, the        device delivers two sprays of the pharmaceutical solution from a        single reservoir. In some embodiments, the bi-dose device has a        first reservoir containing from about 50 μL to about 250 μL of        the pharmaceutical formulation and a second reservoir containing        from about 50 μL to about 250 μL of the pharmaceutical        formulation. In some embodiments, the device delivers one spray        of the pharmaceutical solution from the first reservoir and one        spray of the pharmaceutical solution from the second reservoir.        In some embodiments, the epinephrine, or a pharmaceutically        acceptable salt thereof, is dissolved in water, ethanol,        propylene glycol, or a combination thereof. In some embodiments,        the isotonicity agent is present in a concentration of from        about 0.2% (w/v) to about 1.2% (w/v). In some embodiments, the        pharmaceutical solution further comprises from about 0.1% (w/v)        to about 0.5% (w/v) of a stabilizing agent. In some embodiments,        the pharmaceutical solution further comprises an amount of an        acid sufficient to achieve a pH of from about 3.5 to about 6.5.        In some embodiments, the pharmaceutical solution further        comprises an amount of an acid sufficient to achieve a pH of        from about 3.5 to about 6.5, wherein the acid is hydrochloric        acid or citric acid, or a combination thereof. In some        embodiments, the isotonicity agent is sodium chloride, the        stabilizing agent is disodium edetate, and the acid is        hydrochloric acid or citric acid, or a combination thereof. In        some embodiments, the plasma concentration versus time curve of        epinephrine in the subject has a t_(max) of less than from about        10 minutes to about 120 minutes. In some embodiments, a        therapeutic plasma concentration of epinephrine in the subject        is achieved in less than 20 minutes following administration to        the subject. In some embodiments, a therapeutic plasma        concentration of epinephrine in the subject is achieved in less        than 15 minutes following administration to the subject. In some        embodiments, a therapeutic plasma concentration of epinephrine        in the subject is achieved in less than 10 minutes following        administration to the subject. In some embodiments, a        therapeutic plasma concentration of epinephrine in the subject        is achieved in less than 5 minutes following administration to        the subject. In some embodiments, the therapeutic plasma        concentration of epinephrine in the subject is about 500 pg/mL        of epinephrine. In some embodiments, the therapeutic plasma        concentration of epinephrine in the subject is about 450 pg/mL        of epinephrine. In some embodiments, the therapeutic plasma        concentration of epinephrine in the subject is about 400 pg/mL        of epinephrine. In some embodiments, the therapeutic plasma        concentration of epinephrine in the subject is about 350 pg/mL        of epinephrine. In some embodiments, the therapeutic plasma        concentration of epinephrine in the subject is about 300 pg/mL        of epinephrine. In some embodiments, the subject has a maximum        plasma concentration (Cmax) of from about 50 pg/mL to about 500        pg/mL of epinephrine. In some embodiments, the area under a        plasma concentration-time curve of epinephrine in the subject is        from about 5 ng/minute/mL to about 50 ng/minute/mL. In some        embodiments, the device comprises a plunger that houses a        container closure comprising:        (i) a vial comprising an opening;        (ii) a cannula; and        (iii) a rubber stopper;

wherein the stopper is configured to occlude the opening of the vial,and wherein the cannula is configured such that the cannula can piercethe stopper when the plunger applies sufficient force to the cannula. Insome embodiments, the spray delivers from about 0.5 mg to about 100 mgof epinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the pre-primed device is actuatable with one hand. In someembodiments, the pre-primed device has a single reservoir containingapproximately 125 μL of the pharmaceutical solution. In someembodiments, approximately 100 μL of the pharmaceutical solution isdelivered by one actuation of the device. In some embodiments, thevolume of the reservoir is not more than about 140 μL. In someembodiments, delivery time of the pharmaceutical solution is less thanabout 25 seconds. In some embodiments, delivery time of thepharmaceutical solution is less than about 20 seconds. In someembodiments, less than about 20% of the pharmaceutical solution leavesthe nasal cavity via drainage into the nasopharynx or externally. Insome embodiments, less than about 10% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, less than about 5% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, the subject is suffering from a severe allergicreaction from exposure or suspected exposure to an allergen. In someembodiments, the allergen is food, medication, or an insect bite orsting. In some embodiments, the subject exhibits one or more symptomschosen from: respiratory depression or distress, airway constriction,wheezing, tingling hands, feet, mouth, or scalp, shortness of breath,swelling or inflammation of the face, eyes, lips, tongue, or throat,hives, central nervous system depression, cardiovascular depression,altered level consciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, and vomiting. In some embodiments, the subjectexhibits respiratory depression or distress, or cardiovasculardepression. In some embodiments, the subject is free from respiratorydepression or distress for at least about 1 hour following treatmentcomprising delivery of the therapeutically effective amount of theepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the subject is free from respiratory depression or distressfor at least about 2 hours following treatment comprising delivery ofthe therapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 4 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 6 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is in a lying, supine, or recovery position. In someembodiments, a single spray in the nostril yields a plasma concentrationof ≥0.2 ng/mL within 2.5 minutes in the subject. In some embodiments, asingle spray in the nostril yields a plasma concentration of ≥1 ng/mLwithin 5 minutes in the subject. In some embodiments, a single spray inthe nostril yields a plasma concentration of ≥3 ng/mL within 10 minutesin the subject.

In an aspect provided herein, is a method of treating anaphylaxis- oranaphylactic shock-induced respiratory depression or distress,comprising delivering a spray of a pharmaceutical solution from apre-primed device into a nostril of a subject in need thereof in amanner that delivers the pharmaceutical solution in a round spray plumewith an ovality ratio less than about 2.0 when measured at a distance offrom about 1 to about 10 cm from the pre-primed device, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 μL to about 250 μL of spray is delivered;and

(iii) the pharmaceutical solution comprises from about 0.5 mg to about100 mg of epinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and from about 0.005% (w/v) to about 1% (w/v) ofbenzalkonium chloride. In some embodiments, the device is a single-dosedevice. In some embodiments, the device is a bi-dose device. In someembodiments, the device has a single reservoir containing from about 125μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the device delivers two sprays of the pharmaceuticalsolution from a single reservoir. In some embodiments, the bi-dosedevice has a first reservoir containing from about 50 μL to about 250 μLof the pharmaceutical formulation and a second reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the device delivers one spray of the pharmaceuticalsolution from the first reservoir and one spray of the pharmaceuticalsolution from the second reservoir. In some embodiments, the ovalityratio is less than about 1.5. In some embodiments, the ovality ratio isless than about 1.3. In some embodiments, the ovality ratio is less thanabout 1.2. In some embodiments, the ovality ratio is less than about1.1. In some embodiments, the ovality ratio of the spray is measured ata distance from about 1 cm to about 5 cm from the device.

In another aspect provided herein, is a method for treating at least onesymptom of anaphylaxis or anaphylactic shock comprising delivering aspray of a pharmaceutical solution into a nostril of a subject in needthereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 μL to about 250 μL of spray is delivered;and the pharmaceutical solution comprises from about 0.5 mg to about 100mg of epinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and from about 0.005% (w/v) to about 1% (w/v) ofbenzalkonium chloride. In some embodiments, the device is a single-dosedevice. In some embodiments, the device is a bi-dose device. In someembodiments, the device has a single reservoir containing from about 125μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the device delivers two sprays of the pharmaceuticalsolution from a single reservoir. In some embodiments, the bi-dosedevice has a first reservoir containing from about 50 μL to about 250 μLof the pharmaceutical formulation and a second reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the device delivers one spray of the pharmaceuticalsolution from the first reservoir and one spray of the pharmaceuticalsolution from the second reservoir. In some embodiments, the subject isan adult. In some embodiments, the subject is a child. In someembodiments, the child weighs from about 10 lbs to about 80 lbs.

In another aspect provided herein, is a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising administering or delivering to a subject inneed thereof a pharmaceutical spray formulation described herein. Insome embodiments, the pharmaceutical spray formulation is administeredor delivered into a nostril of the subject from a pre-primed deviceadapted for nasal delivery. In some embodiments, a volume of from about20 μL to about 250 μL of spray is delivered. In some embodiments, theplasma concentration versus time curve of epinephrine in the subject hasa t_(max) of less than from about 10 minutes to about 120 minutes. Insome embodiments, the subject has a maximum plasma concentration (Cmax)of from about 50 pg/mL to about 500 pg/mL of epinephrine. In someembodiments, the area under a plasma concentration-time curve ofepinephrine in the subject is from about 5 ng/minute/mL to about 50ng/minute/mL. In some embodiments, the pre-primed device is actuatablewith one hand. In some embodiments, the pre-primed device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution. In some embodiments, approximately 100 μL ofthe pharmaceutical solution is delivered by one actuation of the device.In some embodiments, the volume of the reservoir is not more than about140 μL. In some embodiments, delivery time of the pharmaceuticalsolution is less than about 25 seconds. In some embodiments, deliverytime of the pharmaceutical solution is less than about 20 seconds. Insome embodiments, less than about 20% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, less than about 10% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, less than about 5% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, the subject is suffering from a severe allergicreaction from exposure or suspected exposure to an allergen. In someembodiments, the allergen is food, medication, or an insect bite orsting. In some embodiments, the subject exhibits one or more symptomschosen from: respiratory depression or distress, airway constriction,wheezing, tingling hands, feet, mouth, or scalp, shortness of breath,swelling or inflammation of the face, eyes, lips, tongue, or throat,hives, central nervous system depression, cardiovascular depression,altered level consciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, and vomiting. In some embodiments, the subjectexhibits respiratory depression or distress, or cardiovasculardepression. In some embodiments, the subject is free from respiratorydepression or distress for at least about 1 hour following treatmentcomprising delivery of the therapeutically effective amount of theepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the subject is free from respiratory depression or distressfor at least about 2 hours following treatment comprising delivery ofthe therapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 4 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 6 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is in a lying, supine, or recovery position. In someembodiments, a single spray in the nostril yields a plasma concentrationof ≥0.2 ng/mL within 2.5 minutes in the subject. In some embodiments, asingle spray in the nostril yields a plasma concentration of ≥1 ng/mLwithin 5 minutes in the subject. In some embodiments, a single spray inthe nostril yields a plasma concentration of ≥3 ng/mL within 10 minutesin the subject.

In another aspect provided herein, is a method of treating anaphylaxis-or anaphylactic shock-induced respiratory depression or distress,comprising administering or delivering to a subject in need thereof aspray formulation described herein from a pre-primed device into anostril of the subject in a manner that delivers the formulation in around spray plume with an ovality ratio less than about 2.0 whenmeasured at a distance of from about 1 to about 10 cm from thepre-primed device, wherein:

(i) the device is adapted for nasal delivery; and

(ii) a volume of from about 20 μL to about 250 μL of spray is delivered.

In some embodiments, the ovality ratio is less than about 1.5. In someembodiments, the ovality ratio is less than about 1.3. In someembodiments, the ovality ratio is less than about 1.2. In someembodiments, the ovality ratio is less than about 1.1. In someembodiments, the ovality ratio of the spray is measured at a distancefrom about 1 cm to about 5 cm from the device.

In another aspect provided herein, is a method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising administeringor delivering to a subject in need thereof the pharmaceutical sprayformulation described herein from a device into a nostril of thesubject, wherein:

(iii) the device is adapted for nasal delivery; and

(iv) a volume of from about 20 μL to about 250 μL of spray is delivered.

In some embodiments, the subject is an adult. In some embodiments, thesubject is a child. In some embodiments, the child weighs from about 10lbs to about 80 lbs.

In another aspect provided herein, is a device as described herein,wherein the device comprises: at least one processor, an operatingsystem configured to perform executable instructions, a memory, and acomputer program including instructions executable by the digitalprocessing device to create an application comprising:

-   -   a) a software module sending a first notification to a portable        device of a user when the device has been triggered for        formulation administration;    -   b) a software module sending a second notification to a second        device of a designated third party when the device has been        triggered for formulation administration;    -   c) a software module sending a third notification to the        portable device of the user when the device is outside a        predetermined range from the portable device;    -   d) a software module sending a fourth notification to the second        device of the designated third party when the device is outside        the predetermined range from the portable device;    -   e) a software module collecting geographic data of the device        when the device is in administration to the user or a second        user;    -   f) a software module saving geographic data of the device to a        remote or cloud database; and    -   g) a software module allowing the user or the second user to        order a new device using the device or the portable device of        the user.

In some embodiments, the portable device or the second device comprisesone or more of: a computer, a notebook computer, a handheld computer, amobile smartphones, a tablet computer, and a personal digital assistant.In some embodiments, the device further comprises a communicationselement configured to allow two-way data communication with the portabledevice of the user and a digital processing device using a wireless datatransfer protocol. In some embodiments, the first, second, third, orfourth notification is sent within the application. In some embodiments,the first, second, third, or fourth notification is automatic. In someembodiments, the first, second, third, or fourth notification comprisesone or more of: text, graphic information, sound, and vibration.

In another aspect of the methods described herein, the method comprises;

-   -   a) sending a first notification to a portable device of a user        when the device has been triggered for formulation        administration;    -   b) sending a second notification to a second device of a        designated third party when the device has been triggered for        formulation administration;    -   c) sending a third notification to the portable device of the        user when the device is outside a predetermined range from the        portable device;    -   d) sending a fourth notification to the second device of the        designated third party when the device is outside the        predetermined range from the portable device;    -   e) collecting geographic data of the device when the device is        in administration to the user or a second user;    -   f) saving geographic data of the device to a remote or cloud        database; and    -   g) allowing the user or the second user to order a new device        using the device or the portable device of the user.

In another aspect provided herein, is a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising delivering a spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a subject in need thereof,wherein: the device is adapted for nasal delivery, a volume of fromabout 20 μL to about 250 μL of spray is delivered, and thepharmaceutical solution comprises the pharmaceutical spray formulationdescribed herein.

In another aspect provided herein, is a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising delivering a spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a subject in need thereof,wherein: the device is adapted for nasal delivery, a volume of fromabout 20 μL to about 250 μL of spray is delivered, and thepharmaceutical solution comprises the pharmaceutical spray formulationdescribed herein.

In an aspect provided herein, is a method of treating anaphylaxis- oranaphylactic shock-induced respiratory depression or distress,comprising delivering a spray of a pharmaceutical solution from apre-primed device into a nostril of a subject in need thereof in amanner that delivers the pharmaceutical solution in a round spray plumewith an ovality ratio less than about 2.0 when measured at a distance offrom about 1 to about 10 cm from the pre-primed device, wherein: thedevice is adapted for nasal delivery, a volume of from about 20 μL toabout 250 μL of spray is delivered, and the pharmaceutical solutioncomprise the pharmaceutical spray formulation described herein.

In another aspect provided herein, is a method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising delivering aspray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein: the device is adapted for nasaldelivery, a volume of from about 20 μL to about 250 μL of spray isdelivered, and the pharmaceutical solution comprise the pharmaceuticalspray formulation described herein.

In an aspect provided herein, is a stable pharmaceutical sprayformulation, comprising: from about 1% to about 25% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, in water; and one or moreexcipients, vehicles, emulsifiers, stabilizing agents, preservatives,mucosal adhesives, antibacterial agents, buffers, and/or otheradditives, wherein the formulation is stable at a temperature of atleast about 20° C. and at a relative humidity of at least about 30%, andwherein the formulation is stable for a period of at least about twomonths, wherein the stable pharmaceutical formulation is thepharmaceutical spray formulation described herein.

In another aspect, disclosed herein is a pharmaceutical sprayformulation, comprising: (i) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (ii) one ormore of an antioxidant, an antimicrobial preservative, an isotonicityagent, an absorption enhancer, a viscosity modifier, or a bufferingagent; wherein the formulation is configured to be administered into anostril of a subject as a nasal spray that yields a plasma concentrationof at least 0.5 ng/mL within 1 minute of administration. In someembodiments, the pH of the formulation is from about 4.0 to about 6.5.In some embodiments, the antioxidant comprises sodium bisulfate orsodium metabisulfite at a concentration from about 0.01% to about 0.1%(w/w). In some embodiments, the antimicrobial preservative compriseschlorobutanol or chlorobutanol hemihydrate at a concentration from about0.1% to about 1% (w/w). In some embodiments, the isotonicity agentcomprises sodium chloride at a concentration from about 0.1% to about 1%(w/w). In some embodiments, the viscosity modifier compriseshypromellose at a concentration from about 0.01% to about 0.2% (w/w). Insome embodiments, the buffering agent comprises citric acid or citricacid monohydrate at a concentration from about 0.1% to about 1% (w/w).In some embodiments, the pharmaceutical spray formulation comprisesabout 2% or about 5% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the pharmaceutical sprayformulation comprises sodium metabisulfite, sodium chloride,hypromellose, citric acid monohydrate, diethylene glycol monoethylether, and chlorobutanol hemihydrate. In some embodiments, thepharmaceutical spray formulation comprises from about 1% to about 10%(w/w) of epinephrine, or a pharmaceutically acceptable salt thereof,from about 0.01% to about 0.1% (w/w) of sodium metabisulfite, from about0.1% to about 1% (w/w) sodium chloride, from about 0.01% to about 0.2%(w/w) hypromellose, from about 0.1% to about 1% (w/w) citric acidmonohydrate, from about 0.1% to about 5% (w/w) diethylene glycolmonoethyl ether, and from about 0.1% to about 1% (w/w) chlorobutanolhemihydrate. In another aspect, disclosed herein is a stablepharmaceutical spray formulation, comprising: (a) from about 1% to about25% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof,in water, ethanol, propylene glycol, or a combination thereof; and (b)one or more of an antioxidant, an antimicrobial preservative, anisotonicity agent, an absorption enhancer, a viscosity modifier, or abuffering agent; wherein the formulation is stable for a period of atleast about one month at a temperature of at least about 20° C. In someembodiments, the formulation is stable for a period of at least onemonth at a temperature of at least about 40° C. In some embodiments, theformulation has no more than about 2% total impurities after storage fora period of at least about one month at a temperature of at least about40° C. In some embodiments, the antioxidant comprises sodium bisulfiteor sodium metabisulfite at a concentration from about 0.01% to about0.1% (w/w). In some embodiments, the antimicrobial preservativecomprises chlorobutanol or chlorobutanol hemihydrate at a concentrationfrom about 0.1% to about 1% (w/w). In some embodiments, the isotonicityagent comprises sodium chloride at a concentration from about 0.1% toabout 1% (w/w). In some embodiments, the buffering agent comprisescitric acid or citric acid monohydrate at a concentration from about0.1% to about 1% (w/w). In another aspect, disclosed herein is apharmaceutical spray formulation, comprising: (i) from about 1% to about25% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof,in water, ethanol, propylene glycol, or a combination thereof and (ii)one or more of an antioxidant, an antimicrobial preservative, anisotonicity agent, an absorption enhancer, a viscosity modifier, or abuffering agent; wherein the absorption enhancer is diethylene glycolmonoethyl ether. In some embodiments, the formulation comprisesdiethylene glycol monoethyl ether at a concentration from about 0.1% toabout 5% (w/w). In some embodiments, the absorption enhancer comprisesdiethylene glycol monoethyl ether at a concentration of about 1% (w/w).

In another aspect, disclosed herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical spray formulation from a nasal spray deviceinto a nostril of a subject in need thereof, wherein the pharmaceuticalspray formulation comprises: (a) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the formulation is configured to be administered into a nostrilof a subject as a nasal spray that yields a plasma concentration of atleast 0.5 ng/mL within 1 minute of administration. In some embodiments,the subject is suffering from a severe allergic reaction from exposureor suspected exposure to an allergen. In some embodiments, the allergenis food, medication, or an insect bite or sting. In some embodiments,the subject exhibits one or more symptoms chosen from: respiratorydepression or distress, airway constriction, wheezing, tingling hands,feet, mouth, or scalp, shortness of breath, swelling or inflammation ofthe face, eyes, lips, tongue, or throat, hives, central nervous systemdepression, cardiovascular depression, altered level consciousness,mydriatic pupils, hypoxemia, hypotension, unresponsiveness to stimulus,unconsciousness, stopped breathing, erratic or stopped pulse, andvomiting. In some embodiments, the subject exhibits respiratorydepression or distress, or cardiovascular depression. In someembodiments, the subject is free from respiratory depression or distressfor at least about 1 hour following delivery of the pharmaceutical sprayformulation. In some embodiments, the antioxidant comprises sodiumbisulfite or sodium metabisulfite at a concentration from about 0.01% toabout 0.1% (w/w). In some embodiments, the antimicrobial preservativecomprises chlorobutanol or chlorobutanol hemihydrate at a concentrationfrom about 0.1% to about 1% (w/w). In some embodiments, the isotonicityagent comprises sodium chloride at a concentration from about 0.1% toabout 1% (w/w). In some embodiments, the viscosity modifier compriseshypromellose at a concentration from about 0.01% to about 0.2% (w/w). Insome embodiments, the buffering agent comprises citric acid or citricacid monohydrate at a concentration from about 0.1% to about 1% (w/w).In some embodiments, the pharmaceutical spray formulation comprisesabout 2% or about 5% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the pharmaceutical sprayformulation comprises sodium metabisulfite, sodium chloride,hypromellose, citric acid monohydrate, diethylene glycol monoethylether, and chlorobutanol hemihydrate. In another aspect, disclosedherein is a method of treating at least one of anaphylaxis, anaphylacticshock, a severe allergic reaction, or bronchial constriction, comprisingadministering or delivering to a subject in need thereof a stablepharmaceutical spray formulation, wherein the stable pharmaceuticalspray formulation comprises: (a) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the formulation is stable for a period of at least about onemonth at a temperature of at least about 20° C. In some embodiments, theformulation is stable for a period of at least one month at atemperature of at least about 40° C. In some embodiments, theformulation comprises no more than 2% total impurities after storage fora period of at least about one month at a temperature of at least about40° C. In another aspect, disclosed herein is a method of treating atleast one of anaphylaxis, anaphylactic shock, a severe allergicreaction, or bronchial constriction, comprising administering ordelivering to a subject in need thereof the pharmaceutical sprayformulation, wherein the pharmaceutical spray formulation comprises: (c)from about 1% to about 25% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof, in water, ethanol, propylene glycol, or acombination thereof; and (d) one or more of an antioxidant, anantimicrobial preservative, an isotonicity agent, an absorptionenhancer, a viscosity modifier, or a buffering agent; wherein atherapeutic plasma concentration of epinephrine in the subject isachieved in less than 15 minutes following administration to thesubject. In some embodiments, the absorption enhancer is diethyleneglycol monoethyl ether. In some embodiments, the formulation comprisesdiethylene glycol monoethyl ether at a concentration from about 0.1% toabout 5% (w/w). In some embodiments, the formulation comprisesdiethylene glycol monoethyl ether at a concentration of about 1% (w/w).

In another aspect, disclosed herein is a bi-dose nasal delivery deviceadapted for delivery of a pharmaceutical solution into a nostril of asubject, comprising: (a) the pharmaceutical solution configured as apharmaceutical spray formulation comprising from about 1% to about 25%(w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, inwater, ethanol, propylene glycol, or a combination thereof; (b) areservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution; and wherein the bi-dose device is configured toadminister the pharmaceutical solution into a nostril of a subject astwo nasal sprays. In some embodiments, the device is a pre-primed devicethat is configured to be actuatable with one hand. In some embodiments,the device is configured to deliver about 100 μL of the pharmaceuticalsolution from the reservoir upon each actuation of the device. In someembodiments, the pH of the pharmaceutical solution is from about 4.0 toabout 6.5. In some embodiments, one or more sprays take the shape of around plume with an ovality ratio less than about 2.0. In someembodiments, the pharmaceutical solution comprises an antioxidant. Insome embodiments, the antioxidant comprises sodium bisulfite or sodiummetabisulfite at a concentration from about 0.01% to about 0.1% (w/w).In some embodiments, the pharmaceutical solution comprises anantimicrobial preservative. In some embodiments, the antimicrobialpreservative comprises chlorobutanol or chlorobutanol hemihydrate at aconcentration from about 0.1% to about 1% (w/w). In some embodiments,the pharmaceutical solution comprises an isotonicity agent. In someembodiments, the isotonicity agent comprises sodium chloride at aconcentration from about 0.1% to about 1% (w/w). In some embodiments,the pharmaceutical solution comprises a viscosity modifier. In someembodiments, the viscosity modifier comprises hypromellose at aconcentration from about 0.01% to about 0.2% (w/w). In some embodiments,the pharmaceutical solution comprises a buffering agent. In someembodiments, wherein the buffering agent comprises citric acid or citricacid monohydrate at a concentration from about 0.1% to about 1% (w/w).In some embodiments, the pharmaceutical solution comprises about 2% orabout 5% (w/w) of epinephrine, or a pharmaceutically acceptable saltthereof. In another aspect, disclosed herein is a pre-primed deviceadapted for delivery of a pharmaceutical solution into one or bothnostrils of a subject, comprising a reservoir containing from about 125μL to about 250 μL of the pharmaceutical solution, wherein thepharmaceutical solution comprises: (a) from about 1% to about 25% (w/w)of epinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the pre-primed device is configured to administer thepharmaceutical solution as one or more sprays into one or both nostrilsof the subject. In some embodiments, the formulation comprisesdiethylene glycol monoethyl ether at a concentration from about 0.1% toabout 5% (w/w). In another aspect, disclosed herein is a bi-dose deviceadapted for delivery of a pharmaceutical solution into one or bothnostrils of a subject, comprising a reservoir containing from about 125μL to about 250 μL of the pharmaceutical solution, wherein thepharmaceutical solution comprises: (a) from about 1% to about 25% (w/w)of epinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the pharmaceutical solution is stable for a period of at leastabout one month at a temperature of at least about 20° C. In someembodiments, the pharmaceutical solution is stable for a period of atleast about three months at a temperature of at least about 20° C.

In another aspect, disclosed herein is a method of administering apharmaceutical solution, comprising delivering a spray of thepharmaceutical solution from a device into a nostril of a subject inneed thereof in a manner that delivers the pharmaceutical solution in around spray plume with an ovality ratio less than about 1.4 whenmeasured at a distance of from about 1 to about 10 cm from the device,wherein: (i) the device is adapted for nasal delivery; (ii) a volume offrom about 20 μL to about 250 μL of spray is delivered; and (iii) thepharmaceutical solution comprises from about 0.5 mg to about 100 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray plume has a particle size distribution with aspan of no more than about 2.2 when measured at a distance of from about1 to about 10 cm from the device. In some embodiments, the spray plumehas a Dmax of less than about 28 mm when measured at a distance of fromabout 1 to about 10 cm from the device. In some embodiments, the deviceis a bi-dose device configured to deliver two sprays of thepharmaceutical solution. In some embodiments, the device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution. In some embodiments, the device comprises aplunger that houses a container closure comprising: (i) a vialcomprising an opening; (ii) a cannula; and (iii) a rubber stopper;wherein the stopper is configured to occlude the opening of the vial,and wherein the cannula is configured such that the cannula can piercethe stopper when the plunger applies sufficient force to the cannula. Insome embodiments, the device is a pre-primed device that is configuredto be actuatable with one hand. In some embodiments, a delivery time ofthe pharmaceutical solution is less than about 25 seconds. In someembodiments, the subject is suffering from a severe allergic reactionfrom exposure or suspected exposure to an allergen. In some embodiments,the allergen is food, medication, or an insect bite or sting. In someembodiments, the subject exhibits one or more symptoms chosen from:respiratory depression or distress, airway constriction, wheezing,tingling hands, feet, mouth, or scalp, shortness of breath, swelling orinflammation of the face, eyes, lips, tongue, or throat, hives, centralnervous system depression, cardiovascular depression, altered levelconsciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, or vomiting. In some embodiments, the subjectexhibits respiratory depression or distress, or cardiovasculardepression. In some embodiments, the subject is free from respiratorydepression or distress for at least about 1 hour following treatmentcomprising delivery of a therapeutically effective amount of theepinephrine, or a pharmaceutically acceptable salt thereof. In anotheraspect, disclosed herein is a method of administering a pharmaceuticalsolution, comprising delivering a spray of the pharmaceutical solutionfrom a device into a nostril of a subject in need thereof in a mannerthat delivers the pharmaceutical solution in a spray plume with aparticle size distribution having a span of no more than about 2.2 whenmeasured at a distance of from about 1 to about 10 cm from the device,wherein: (i) the device is adapted for nasal delivery; (ii) a volume offrom about 20 μL to about 250 μL of spray is delivered; and (iii) thepharmaceutical solution comprises from about 0.5 mg to about 100 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the particle size distribution has a span of no more thanabout 2.0 when measured at a distance of from about 1 to about 10 cmfrom the device. In some embodiments, the device has a single reservoircontaining from about 125 μL to about 250 μL of the pharmaceuticalsolution. In some embodiments, the device is a bi-dose device configuredto deliver two sprays of the pharmaceutical solution from a singlereservoir. In another aspect, disclosed herein is a method foradministering a pharmaceutical solution, comprising delivering a sprayof the pharmaceutical solution from a device into a nostril of a subjectin need thereof in a manner that delivers the pharmaceutical solution ina spray plume with a Dmax of less than about 28 mm when measured at adistance of from about 1 to about 10 cm from the device, wherein: (i)the device is adapted for nasal delivery; (ii) a volume of from about 20μL to about 250 μL of spray is delivered; and (iii) the pharmaceuticalsolution comprises from about 0.5 mg to about 100 mg of epinephrine, ora pharmaceutically acceptable salt thereof. In some embodiments, thedevice is a bi-dose device configured to deliver two sprays of thepharmaceutical solution. In some embodiments, the Dmax is less thanabout 26 mm when measured at a distance of from about 1 to about 10 cmfrom the device.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

A better understanding of the features and advantages of the presentsubject matter will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments and theaccompanying drawings.

FIG. 1 depicts plasma concentrations of epinephrine in dogs dosed with 5mg in a single nostril of a formulation described in Example 3(Formulation 2) versus plasma concentrations of epinephrine in dogsdosed with EpiPen Adult (0.3 mg/mL).

FIG. 2 depicts plasma concentrations of epinephrine in dogs dosed with10 mg in a single nostril of a formulation described in Example 3(Formulation 2) versus plasma concentrations of epinephrine in dogsdosed with EpiPen Adult (0.3 mg/mL).

FIG. 3 shows a diagram of a congestion test system.

FIG. 4 shows the results of epinephrine inhibition of histamine inducednasal congestion.

FIG. 5 shows a chart of individual heart rates for beagles exposed tohistamine and treated with epinephrine.

FIG. 6 shows a chart of individual heart rates for beagles exposed tosaline (control) and treated with epinephrine.

FIG. 7 shows a chart of mean heart rates comparing exposure to histamineand saline.

FIG. 8 shows plasma epinephrine concentration profiles over time forindividual animals within group 1.

FIG. 9 shows plasma epinephrine concentration profiles over time forindividual animals within group 2.

FIG. 10 shows group average epinephrine concentration profiles over timefor the two study groups.

FIG. 11 shows Student's t-test comparing: A) AUC, B) C_(max), and C)T_(max) between two study groups.

FIG. 12 shows pre- and post-dose plasma levels of epinephrine in CSF.

FIG. 13 shows mean heart rates over time before and after 4 mgepinephrine dose compared to baseline for SD29-30 for the overall study(intranasal administration).

FIG. 14 shows mean heart rates over time before and after 5 mgepinephrine dose compared to baseline for SD29-30 for the overall study(intranasal administration).

FIG. 15 shows mean heart rates over time before and after 0.3 mgepinephrine dose compared to baseline for SD29-30 for the overall study(intramuscular administration).

FIG. 16 shows individual plasma concentration-time profiles comparinganimals treated with epinephrine via intranasal administration andanimals treated with epinephrine via intramuscular injection.

FIG. 17 shows an illustrative diagram of a nasal spray delivery device.

DETAILED DESCRIPTION

Provided herein are, for example, pharmaceutical spray formulations ofepinephrine for treating anaphylaxis. Also provided herein are, forexample, methods of treating anaphylaxis, anaphylactic shock, and/or asevere allergic reaction, or at least one symptom thereof.

I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

The terms “about” or “approximately” as used herein, when referring to anumerical value or range, allow for a degree of variability in the valueor range, for example, within 10%, or within 5% of a stated value or ofa stated limit of a range.

The term “actuation,” as used herein, refers to operation of the devicesuch that the pharmaceutical composition is delivered therefrom.

The term “AUC,” as used herein, refers to the area under the drug (e.g.,epinephrine) plasma concentration-time curve. The term “AUC_(0-t),” asused herein, refers to the area under the drug plasma concentration-timecurve from t=0 to the last measurable concentration. The term“AUC_(0-∞),” as used herein, refers to the area under the drug plasmaconcentration-time curve extrapolated to co.

The term “bioavailability (F),” as used herein, refers to the fractionof a dose of drug (e.g., epinephrine) that is absorbed from its site ofadministration and reaches, in an unchanged form, the systemiccirculation. The term “absolute bioavailability” is used when thefraction of absorbed drug is related to its I.V. bioavailability. It maybe calculated using the following formula:

$F = {\frac{{AUC}_{extravascular}}{{AUC}_{intravenous}} \times \frac{{Dose}_{intravenous}}{{Dose}_{extravascular}}}$

The term relative bioavailability (F_(rel)) is used to compare twodifferent extravascular routes of drug administration and it may becalculated using the following formula:

$F_{rel} = {\frac{{AUC}_{{extravascular}\mspace{11mu} 1}}{{AUC}_{{extravascular}\mspace{11mu} 2}} \times \frac{{Dose}_{{extravascular}\mspace{11mu} 2}}{{Dose}_{{extravascular}\mspace{11mu} 1}}}$

The term “clearance (CL),” as used herein, refers to the rate at which adrug is eliminated divided by its plasma concentration, giving a volumeof plasma from which drug is completely removed per unit of time. CL isequal to the elimination rate constant (λ) multiplied by the volume ofdistribution (V_(d)), wherein “V_(d)” is the fluid volume that would berequired to contain the amount of drug present in the body at the sameconcentration as in the plasma. The term “apparent clearance (CL/F),” asused herein, refers to clearance that does not take into account thebioavailability of the drug. It is the ratio of the dose over the AUC.

The term “C_(max),” as used herein, refers to the maximum observedplasma concentration.

The term “coefficient of variation (CV),” as used herein, refers to theratio of the sample standard deviation to the sample mean. It is oftenexpressed as a percentage.

The term “confidence interval,” as used herein, refers to a range ofvalues which will include the true average value of a parameter aspecified percentage of the time.

The term “device,” as used herein, refers to an apparatus capable ofdelivering a drug to patient in need thereof.

The term “delivery time,” as used herein, refers to the amount of timethat elapses between a determination made by a healthcare professional,or an untrained individual that an individual is in need of nasaldelivery of epinephrine and completion of the delivery.

The term “elimination rate constant (λ),” as used herein, refers to thefractional rate of drug removal from the body. This rate is constant infirst-order kinetics and is independent of drug concentration in thebody. λ is the slope of the plasma concentration-time line (on alogarithmic y scale). The term “λ_(z),” as used herein, refers to theterminal phase elimination rate constant, wherein the “terminal phase”of the drug plasma concentration-time curve is a straight line whenplotted on a semi-logarithmic graph. The terminal phase is often calledthe “elimination phase” because the primary mechanism for decreasingdrug concentration during the terminal phase is drug elimination fromthe body. The distinguishing characteristic of the terminal eliminationphase is that the relative proportion of drug in the plasma andperipheral volumes of distribution remains constant. During this“terminal phase” drug returns from the rapid and slow distributionvolumes to the plasma, and is permanently removed from the plasma bymetabolism or renal excretion.

The term “epinephrine,” as used herein, refers to a compound of thefollowing structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. TheCAS registry number for epinephrine is 51-43-4. Other names forepinephrine include, but are not limited to,(R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol and adrenaline.

The term “nostril,” as used herein, is synonymous with “naris.”

The terms “permeation enhancer”, “permeability enhancer”, “absorptionenhancer”, and “penetration enhancer,” as disclosed herein, are intendedto be equivalent, all four referring to an agent which aids indelivering and/or increasing bioavailability and C_(max) of a compoundthrough a mucosal barrier, such as through the nasal mucosa. Permeationor absorption enhancers suitable for use in the present inventioninclude, but are not limited to, caprylic acid, oleic acid, polysorbate80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, sodiumlauryl sulfate, citric acid, sodium desoxycholate, sodiumdeoxyglycolate, glyceryl oleate, L-lysine, diethylene glycol monoethylether, α- β- or γ-cyclodextrin, hydroxypropyl β-cyclodextrin,phosphatidylcholine, and combinations thereof. In some cases, theabsorption enhancer comprises diethylene glycol monoethyl ether. In somecases, use of absorption enhancers can reduce T_(max). In some cases,use of absorption enhancers decreases the time within which a givenplasma concentration of the active ingredient is achieved followingadministration. Absorption enhancers may be used to increase the AUC ofthe active ingredient.

The term “stabilizer” and “stabilizing agent” are intended to beequivalent and refer to a chemical that is used to prevent degradation.Examples of stabilizers or stabilizing agents include, but are notlimited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate,sodium bisulfate, sodium metabisulfite, ascorbyl palmitate,thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride,citric acid, ethylenediaminetetraacetic acid (“EDTA”), sodium citrate,propyl gallate, 8-hydroxyquinoline, boric acid, histidine, vitamin A,and combinations thereof.

The term “viscosity modifier” refers to a product or combination ofproducts designed to change the thickness or texture of pharmaceuticalingredients or formulations. Viscosity modifiers can include suchproducts as thickeners, texturizers, gelation agents and stiffeningagents. Examples of viscosity modifiers include, but are not limited to,polyethylene glycol, methylcellulose, hypromellose,polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropylmethylcellulose (“HPMC”), methyl cellulose, hydroxyethyl cellulose, glycerin,polyvinyl alcohol, xanthan gum, chitosan, alginate, and combinationsthereof.

Solvents suitable for use in the present invention include, but are notlimited to, water, ethanol, glycerin, propylene glycol, polyethyleneglycol 400 and combinations thereof.

The term “pre-primed,” as used herein, refers to a device, such as anasal spray which is capable of delivering a pharmaceutical compositionto a patient in need thereof with the first actuation of the spray pump,i.e., without the need to prime the pump prior to dosing, such as byactuating the pump one or more times until a spray appears.

The term “recovery position,” as used herein, means a position of thehuman body in which a patient lies on his/her side, with a leg or kneeout in front (e.g., to prevent rolling onto his/her stomach) and atleast one hand supporting the head (e.g., to elevate the face tofacilitate breathing and prevent inhalation of vomit).

The term “storage-stable,” as used herein, refers to a pharmaceuticalcomposition in which at least about 95%—for example at least about99.5%—of the active ingredient remains in an undegraded state afterstorage of the pharmaceutical composition at specified temperature andhumidity for a specified time, for example, for 12 months at 25° C. and60% relative humidity.

The term “supine,” as used herein, refers to a patient who is lying faceup.

The term “t_(1/2)” or “half-life,” as used herein, refers to the amountof time required for half of a drug to be eliminated from the body orthe time required for a drug concentration to decline by half.

The terms “tonicity agent” and “isotonicity agent” as used herein areinterchangeable and refer to a compound which modifies the osmolality ofa formulation, for example, to render it isotonic. Tonicity agentsinclude, but are not limited to, dextrose, lactose, sodium chloride,calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol,trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycineand the like.

The term “t_(max),” as used herein, refers to the time fromadministration of the pharmaceutical compositions described herein tomaximum drug plasma concentration.

Liquid nasal formulations are mainly aqueous solutions, but suspensionsand emulsions can also be delivered. In traditional spray pump systems,antimicrobial preservatives are typically required to maintainmicrobiological stability in liquid formulations.

The droplet size distribution of a nasal spray influences the in vivodeposition of the drug in the nasal cavity. The droplet size isinfluenced by the actuation parameters of the device and theformulation. In some embodiments, the median droplet size is from about30 to about 100 μm. If the droplets are too large (e.g., greater thanabout 120 μm), deposition takes place mainly in the anterior parts ofthe nose, and if the droplets are too small (e.g., less than about 10μm), they can possibly be inhaled and reach the lungs.

Spray characterization (e.g., plume geometry, spray pattern, pumpdelivery, droplet size distribution, DSD) of the delivered plumesubsequent to spraying may be measured under specified experimental andinstrumental conditions by appropriate and validated and/or calibratedanalytical procedures known in the art. These include photography, laserdiffraction, and impaction systems (cascade impaction, next generationimpaction (NGI), etc.). Droplet size distribution can be controlled interms of ranges for the D10, D50, D90, span [(D90-D10)/D50], andpercentage of droplets less than 10 mm. In some embodiments, theformulation will have a narrow DSD. In some embodiments, the formulationwill have a Dv(50) of 30-70 μm and a Dv(90)<120 μm. The particlediameter “(D)” designations refer to the representative diameter where10% (D10), 50% (D50) and 90% (D90) of the total volume of the liquidsprayed is made up of droplets with diameters smaller than or equal tothe stated value. The spray characteristics can refer to a mean(average) or median value collected for a plurality of sprays. Theplurality of sprays can be at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or moresprays.

All percent compositions are given as weight-percentages, unlessotherwise stated.

All average molecular weights of polymers are weight-average molecularweights, unless otherwise specified.

As used herein, “subject” or “patient” (as in the subject of thetreatment) means both mammals and non-mammals. Mammals include, forexample, humans; non-human primates, e.g. apes and monkeys; andnon-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.Non-mammals include, for example, fish and birds. Terms “subject” and“patient” are synonymous and refer, but are not limited to, a personthat is experiencing type I allergies including anaphylaxis. “Patient”or “subject in need thereof” refers to a living organism suffering fromor prone to a disease or condition that can be treated by administrationof a pharmaceutical composition as provided herein. In some embodiments,a patient is human.

The terms “disease,” “disorder,” or “condition” are used interchangeablyand refer to a state of being or health status of a patient or subjectcapable of being treated with the compounds or methods provided herein.The disease may be anaphylaxis. The disease may be a severe allergicreaction, and the like. The disease may be a cancer. The disease may bean autoimmune disease. The disease may be an inflammatory disease. Thedisease may be an infectious disease.

As used herein, “type I reactions,” “type I allergies,” and “severeallergic reactions” are used interchangeably (i.e., immediatehypersensitivity reactions) and refer to the involvement ofimmunoglobulin E (IgE)-mediated release of histamine and other mediatorsfrom mast cells and basophils. Examples include, but are not limited to,anaphylaxis, an anaphylactic reaction, anaphylactic shock and allergicrhinoconjunctivitis. Severe allergic reactions are caused by allergens.Non-limiting examples of allergens include an insect bite (for example abee sting), medication (for example an antibiotic such as a penicillin),food (such as eggs, nuts, or shellfish), and a chemical (for examplelatex).

As used herein, “free of propellant” refers to a formulation that is notadministered using compressed gas.

The terms “spray” and “mist” are used interchangeably herein and referto liquid (e.g., a formulation for intranasal administration) that isblown or driven through the air in the form of drops or droplets.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” or “approximately” each particularvalue is plus or minus 10%. For example, the phrase “about 10% w/w” isto be understood as “9% w/w to 11% w/w.” Therefore, amounts within 10%of the claimed value are encompassed by the scope of the claims.

As used herein “% w/w” and “percent w/w” refer to the percent weight ofthe total formulation.

As used herein the term “effective amount” refers to the amountnecessary to treat a patient in need thereof.

The terms “treating” or “treatment” refer to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease. In some embodiments, treatingis preventing. In some embodiments, treating does not includepreventing. In some embodiments, “treat,” “treating,” or “treatment”refer to ameliorating or inhibiting symptoms of type I allergiesincluding anaphylaxis.

“Treating” or “treatment” as used herein (and as well-understood in theart) also broadly includes any approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. In other words, “treatment” as used herein includes anycure, amelioration, or prevention of a disease. Treatment may preventthe disease from occurring; inhibit the disease's spread; relieve thedisease's symptoms (e.g., throat or tongue swelling, itchy rash,shortness of breath, low blood pressure, inflammation,bronchoconstriction, etc.), fully or partially remove the disease'sunderlying cause, shorten a disease's duration, or do a combination ofthese things.

“Treating” and “treatment” as used herein include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of a compound described herein. Theadministering step may consist of a single administration or may includea series of administrations. The length of the treatment period dependson a variety of factors, such as the severity of the condition, the ageof the patient, the concentration of the compound, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

The term “prevent” refers to a decrease in the occurrence of diseasesymptoms in a patient. As indicated above, the prevention may becomplete (no detectable symptoms) or partial, such that fewer symptomsare observed than would likely occur absent treatment. In someembodiments, prevent refers to slowing the progression of the disease,disorder or condition or inhibiting progression thereof to a harmful orotherwise undesired state.

An “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g., achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. Theexact amounts will depend on the purpose of the treatment, and will beascertainable by one skilled in the art using known techniques (see,e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd,The Art, Science and Technology of Pharmaceutical Compounding (1999);Pickar, Dosage Calculations (1999); and Remington: The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,Williams & Wilkins). The therapeutically effective amount can beascertained by measuring relevant physiological effects, and it can beadjusted in connection with the dosing regimen and diagnostic analysisof the subject's condition, and the like.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan. Adjusting the dose to achieve maximal therapeutic windowefficacy or toxicity in humans based on the methods described above andother methods is well within the capabilities of the ordinarily skilledartisan.

The term “therapeutically effective amount,” as used herein, refers tothat amount of the therapeutic agent sufficient to ameliorate thedisorder, as described above. For example, for the given parameter, atherapeutically effective amount will show an increase or decrease of atleast 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least100%. Therapeutic efficacy can also be expressed as “-fold” increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means administration byinhalation or intranasal administration. The term “intranasal” refers toadministration of the composition to any portion of the nasalepithelium.

Administering may also mean oral administration, administration as asuppository, topical contact, intravenous, parenteral, intraperitoneal,intramuscular, intralesional, intrathecal, intracranial, or subcutaneousadministration, or the implantation of a slow-release device, e.g., amini-osmotic pump, to a subject. Administration is by any route,including parenteral and transmucosal (e.g., buccal, sublingual,palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteraladministration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, subcutaneous, intraperitoneal,intraventricular, and intracranial. Other modes of delivery include, butare not limited to, the use of liposomal formulations, intravenousinfusion, transdermal patches, etc. By “co-administer” it is meant thata composition described herein is administered at the same time, justprior to, or just after the administration of one or more additionaltherapies (e.g. anti-inflammatory agent). The compound of the inventioncan be administered alone or can be co-administered to the patient.Co-administration is meant to include simultaneous or sequentialadministration of the compound individually or in combination (more thanone compound or agent). Thus, the preparations can also be combined,when desired, with other active substances (e.g. to reduce metabolicdegradation). Liquid form preparations include solutions, suspensions,and emulsions. In some embodiments, the compositions are water orwater/propylene glycol solutions. The compositions of the presentinvention may additionally include components to provide sustainedrelease and/or comfort.

By “co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of thedisclosure can be administered alone or can be co-administered to thepatient. Co-administration is meant to include simultaneous orsequential administration of the compounds individually or incombination (more than one compound).

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4days, 1 week or 1 month of a second active agent. Co-administrationincludes administering two active agents simultaneously, approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other), or sequentially in any order. In some embodiments,co-administration can be accomplished by co-formulation, i.e., preparinga single pharmaceutical composition including both active agents. Inother embodiments, the active agents can be formulated separately. Inanother embodiment, the active and/or adjunctive agents may be linked orconjugated to one another.

“Anti-inflammatory agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) used in any way to reduce inflammation orswelling. In some embodiments, an anti-inflammatory agent is an agentidentified herein having utility in methods of treating an inflammatorydisease or disorder. In some embodiments, an anti-inflammatory agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for reducing swelling and inflammation.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present disclosure should be sufficient to affect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

As used herein the term “anaphylaxis” refers to an allergic reactioninvolving multiple organ systems in a subject upon contact with anallergen whether or not that allergen is identifiable.

As used herein the term “allergen” refers to any chemical capable ofcausing an immune system response in a subject including, but notlimited to, chemicals found in drugs, food, plants, insect bites, andinsect stings.

As used herein the term “pharmaceutically acceptable” refers toingredients that are not biologically or otherwise undesirable foradministration to a living subject.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present disclosure contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present disclosure may exist as salts, suchas with pharmaceutically acceptable acids. The present disclosureincludes such salts. Non-limiting examples of such salts includehydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, proprionates,tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereofincluding racemic mixtures), succinates, benzoates, and salts with aminoacids such as glutamic acid, and quaternary ammonium salts (e.g. methyliodide, ethyl iodide, and the like). These salts may be prepared bymethods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents. In some embodiments, compounds of thepresent disclosure contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts. The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in a conventional manner. The parent form of the compoundsdiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but, unless specifically indicated, thesalts disclosed herein are equivalent to the parent form of the compoundfor the purposes of the present disclosure.

In some embodiments, epinephrine salts may include citrate,hydrochloride, sulfate, tartrate, phosphate, acetate, malate, maleate,succinate, ascorbate, carbonate, mesylate, and lactate salts. One ofskill in the art could use other pharmaceutically acceptable epinephrinesalts in the formulations disclosed herein.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present disclosure by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of a compoundto and absorption by a subject and can be included in the compositionsof the present disclosure without causing a significant adversetoxicological effect on the patient. Such preparations can be sterilizedand, if desired, mixed with auxiliary agents such as lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, coloring, and/or aromaticsubstances and the like that do not deleteriously react with thecompounds of the disclosure. One of skill in the art will recognize thatother pharmaceutical excipients are useful in the present disclosure.Examples of preservatives include, but are not limited to, butylparaben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate,chlorobutanol, benzalkonium chloride, benzoic acid and combinationsthereof.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

II. Compositions

In an aspect provided herein, is a pharmaceutical spray formulation. Insome embodiments, the pharmaceutical spray formulation comprisesepinephrine, or a pharmaceutically acceptable salt of epinephrine, inwater, ethanol, propylene glycol, or a combination thereof. In someembodiments, the pH of the pharmaceutical spray formulation is about 3.5to about 6.5.

In some aspects, the pharmaceutical spray formulation comprises anactive ingredient. In some embodiments, the active ingredient isepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises from about 0.5% to about 25% w/w of epinephrine. In someembodiments, the pharmaceutical spray formulation comprises from about0.5% to about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 0.5% to about 10%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 1.0% to about 25% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 1.0% to about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 1.0% to about 10%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 2.0% to about 25% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 2.0% to about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 2.0% to about 10%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 3.0% to about 25% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 3.0% to about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 3.0% to about 10%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 4.0% to about 25% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 4.0% to about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 4.0% to about 25%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 4.0% to about 20% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 4.0% to about 10% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 5.0% to about 25%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 5.0% to about 20% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprises fromabout 5.0% to about 10% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises from about 0.5% to about 5%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises from about 1.0% to about 5% w/w of epinephrine. Insome embodiments, the pharmaceutical spray formulation comprises fromabout 2.0% to about 5% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 0.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 0.5% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 1% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprisesabout 1.5% w/w of epinephrine. In some embodiments, the pharmaceuticalspray formulation comprises about 2% w/w of epinephrine. In someembodiments, the pharmaceutical spray formulation comprises about 2.5%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises about 3% w/w of epinephrine. In some embodiments,the pharmaceutical spray formulation comprises about 3.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 4% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 4.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 5% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 6.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 7% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 7.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 8% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 8.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 9% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 9.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 10% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 10.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 11% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 11.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 12% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 12.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 13% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 13.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 14% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 14.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 15% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 15.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 16% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 16.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 17% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 17.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 18% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 18.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 19% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 19.5% w/w ofepinephrine. In some embodiments, the pharmaceutical spray formulationcomprises about 20% w/w of epinephrine. In some embodiments, thepharmaceutical spray formulation comprises about 21% w/w of epinephrine.In some embodiments, the pharmaceutical spray formulation comprisesabout 22% w/w of epinephrine. In some embodiments, the pharmaceuticalspray formulation comprises about 23% w/w of epinephrine. In someembodiments, the pharmaceutical spray formulation comprises about 24%w/w of epinephrine. In some embodiments, the pharmaceutical sprayformulation comprises about 25% w/w of epinephrine.

In an aspect provided herein, is a stable pharmaceutical sprayformulation, comprising:

-   -   (i) from about 1% to about 25% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof, in water, ethanol,        propylene glycol, or a combination thereof; and    -   (ii) one or more excipients, vehicles, emulsifiers, stabilizing        agents, preservatives, mucosal adhesives, antibacterial agents,        buffers, and/or other additives, wherein the formulation is        stable at a temperature of at least about 20° C. and at a        relative humidity of at least about 30%, and wherein the        formulation is stable for a period of at least about two months.

In an aspect provided herein, is a stable pharmaceutical sprayformulation, comprising:

-   -   (iii) from about 1% to about 10% w/w of epinephrine, or a        pharmaceutically acceptable salt thereof, in water, ethanol,        propylene glycol, or a combination thereof; and    -   (iv) one or more excipients, vehicles, emulsifiers, stabilizing        agents, preservatives, mucosal adhesives, antibacterial agents,        buffers, and/or other additives, wherein the formulation is        stable at a temperature of at least about 20° C. and at a        relative humidity of at least about 30%, and wherein the        formulation is stable for a period of at least about two months.

In some embodiments, the pharmaceutical spray formulation is stable at atemperature of at least about 25° C. In some embodiments, thepharmaceutical spray formulation is stable at a temperature of at leastabout 30° C. In some embodiments, the pharmaceutical spray formulationis stable at a temperature of at least about 35° C. In some embodiments,the pharmaceutical spray formulation is stable at a temperature of atleast about 40° C. In some embodiments, the pharmaceutical sprayformulation is stable at a temperature of at least about 45° C.

In some embodiments, the pharmaceutical spray formulation is stable at arelative humidity of at least about 40%. In some embodiments, thepharmaceutical spray formulation is stable at a relative humidity of atleast about 50%. In some embodiments, the pharmaceutical sprayformulation is stable at a relative humidity of at least about 60%. Insome embodiments, the pharmaceutical spray formulation is stable at arelative humidity of at least about 70%. In some embodiments, thepharmaceutical spray formulation is stable at a relative humidity of atleast about 80%.

In some embodiments, the pharmaceutical spray formulation is stable fora period of at least about six months. In some embodiments, thepharmaceutical spray formulation is stable for a period of at leastabout 12 months. In some embodiments, the pharmaceutical sprayformulation is stable for a period of at least about 18 months. In someembodiments, the pharmaceutical spray formulation is stable for a periodof at least about 24 months. In some embodiments, the pharmaceuticalspray formulation is stable for a period of at least about 30 months. Insome embodiments, the pharmaceutical spray formulation is stable for aperiod of at least about 36 months.

Viscosity Modifiers

In some embodiments, the pharmaceutical spray formulation comprises aviscosity modifier. Viscosity modifiers can include such products asthickeners, texturizers, gelation agents and stiffening agents. In someembodiments, the viscosity modifier is polyethylene glycol,methylcellulose, hypromellose, polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylmethyl cellulose (“HPMC”), methyl cellulose,hydroxyethyl cellulose, glycerin, polyvinyl alcohol, xanthan gum,chitosan, alginate, or any combinations thereof. In some embodiments,the viscosity modifier is polyethylene glycol. In some embodiments, theviscosity modifier is methylcellulose. In some embodiments, theviscosity modifier is hypromellose. In some embodiments, the viscositymodifier is polyvinylpyrrolidone. In some embodiments, the viscositymodifier is carboxymethyl cellulose. In some embodiments, the viscositymodifier is hydroxypropylmethyl cellulose. In some embodiments, theviscosity modifier is methyl cellulose. In some embodiments, theviscosity modifier is hydroxyethyl cellulose. In some embodiments, theviscosity modifier is glycerin. In some embodiments, the viscositymodifier is polyvinyl alcohol. In some embodiments, the viscositymodifier is xanthan gum. In some embodiments, the viscosity modifier ischitosan. In some embodiments, the viscosity modifier is alginate.

In some embodiments, the pharmaceutical spray formulation comprisesabout 0.001% (w/w) to about 1% (w/w) of a viscosity modifier. In someembodiments, the pharmaceutical spray formulation comprises about 0.001%(w/w) to about 0.5% (w/w) of a viscosity modifier. In some embodiments,the pharmaceutical spray formulation comprises about 0.001% (w/w) toabout 1% (w/w) of a viscosity modifier. In some embodiments, thepharmaceutical spray formulation comprises about 0.01% (w/w) to about 1%(w/w) of a viscosity modifier. In some embodiments, the pharmaceuticalspray formulation comprises about 0.01% (w/w) to about 0.5% (w/w) of aviscosity modifier. In some embodiments, the pharmaceutical sprayformulation comprises about 0.1% (w/w) of a viscosity modifier. In someembodiments, the pharmaceutical spray formulation comprises at leastabout 0.001% (w/w), at least about 0.01% (w/w), or at least about 0.1%(w/w), and/or no more than about 5% (w/w), no more than about 1% (w/w),no more than about 0.5% (w/w), no more than about 0.4% (w/w), no morethan about 0.3% (w/w), no more than about 0.2% (w/w), or no more thanabout 0.1% (w/w) of a viscosity modifier.

In some embodiments, the pharmaceutical spray formulation comprises aviscosity modifier at a concentration of about 0.001% (w/w) to about 2%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises a viscosity modifier at a concentration of at least about0.001% (w/w). In some embodiments, the pharmaceutical spray formulationcomprises a viscosity modifier at a concentration of at most about 2%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises a viscosity modifier at a concentration of about 0.001% (w/w)to about 0.01% (w/w), about 0.001% (w/w) to about 0.05% (w/w), about0.001% (w/w) to about 0.06% (w/w), about 0.001% (w/w) to about 0.07%(w/w), about 0.001% (w/w) to about 0.08% (w/w), about 0.001% (w/w) toabout 0.09% (w/w), about 0.001% (w/w) to about 0.1% (w/w), about 0.001%(w/w) to about 0.5% (w/w), about 0.001% (w/w) to about 1% (w/w), about0.001% (w/w) to about 1.5% (w/w), about 0.001% (w/w) to about 2% (w/w),about 0.01% (w/w) to about 0.05% (w/w), about 0.01% (w/w) to about 0.06%(w/w), about 0.01% (w/w) to about 0.07% (w/w), about 0.01% (w/w) toabout 0.08% (w/w), about 0.01% (w/w) to about 0.09% (w/w), about 0.01%(w/w) to about 0.1% (w/w), about 0.01% (w/w) to about 0.5% (w/w), about0.01% (w/w) to about 1% (w/w), about 0.01% (w/w) to about 1.5% (w/w),about 0.01% (w/w) to about 2% (w/w), about 0.05% (w/w) to about 0.06%(w/w), about 0.05% (w/w) to about 0.07% (w/w), about 0.05% (w/w) toabout 0.08% (w/w), about 0.05% (w/w) to about 0.09% (w/w), about 0.05%(w/w) to about 0.1% (w/w), about 0.05% (w/w) to about 0.5% (w/w), about0.05% (w/w) to about 1% (w/w), about 0.05% (w/w) to about 1.5% (w/w),about 0.05% (w/w) to about 2% (w/w), about 0.06% (w/w) to about 0.07%(w/w), about 0.06% (w/w) to about 0.08% (w/w), about 0.06% (w/w) toabout 0.09% (w/w), about 0.06% (w/w) to about 0.1% (w/w), about 0.06%(w/w) to about 0.5% (w/w), about 0.06% (w/w) to about 1% (w/w), about0.06% (w/w) to about 1.5% (w/w), about 0.06% (w/w) to about 2% (w/w),about 0.07% (w/w) to about 0.08% (w/w), about 0.07% (w/w) to about 0.09%(w/w), about 0.07% (w/w) to about 0.1% (w/w), about 0.07% (w/w) to about0.5% (w/w), about 0.07% (w/w) to about 1% (w/w), about 0.07% (w/w) toabout 1.5% (w/w), about 0.07% (w/w) to about 2% (w/w), about 0.08% (w/w)to about 0.09% (w/w), about 0.08% (w/w) to about 0.1% (w/w), about 0.08%(w/w) to about 0.5% (w/w), about 0.08% (w/w) to about 1% (w/w), about0.08% (w/w) to about 1.5% (w/w), about 0.08% (w/w) to about 2% (w/w),about 0.09% (w/w) to about 0.1% (w/w), about 0.09% (w/w) to about 0.5%(w/w), about 0.09% (w/w) to about 1% (w/w), about 0.09% (w/w) to about1.5% (w/w), about 0.09% (w/w) to about 2% (w/w), about 0.1% (w/w) toabout 0.5% (w/w), about 0.1% (w/w) to about 1% (w/w), about 0.1% (w/w)to about 1.5% (w/w), about 0.1% (w/w) to about 2% (w/w), about 0.5%(w/w) to about 1% (w/w), about 0.5% (w/w) to about 1.5% (w/w), about0.5% (w/w) to about 2% (w/w), about 1% (w/w) to about 1.5% (w/w), about1% (w/w) to about 2% (w/w), or about 1.5% (w/w) to about 2% (w/w). Insome embodiments, the pharmaceutical spray formulation comprises aviscosity modifier at a concentration of about 0.001% (w/w), about 0.01%(w/w), about 0.05% (w/w), about 0.06% (w/w), about 0.07% (w/w), about0.08% (w/w), about 0.09% (w/w), about 0.1% (w/w), about 0.5% (w/w),about 1% (w/w), about 1.5% (w/w), or about 2% (w/w). In someembodiments, the viscosity modifier is hypromellose.

In some embodiments, the pharmaceutical spray formulation has aviscosity of at least about 100 cP, at least about 250 cP, at leastabout 500 cP, at least about 750 cP, at least about 1000 cP, at leastabout 1250 cP, at least about 1500 cP, at least about 1750 cP, at leastabout 2000 cP, at least about 2250 cP, or at least about 2500 cP, and/orno more than about 100 cP, no more than about 250 cP, no more than about500 cP, no more than about 750 cP, no more than about 1000 cP, no morethan about 1250 cP, no more than about 1500 cP, no more than about 1750cP, no more than about 2000 cP, no more than about 2250 cP, or no morethan about 2500 cP.

In some embodiments, the pharmaceutical spray formulation has aviscosity of about 100 cP to about 2,500 cP. In some embodiments, thepharmaceutical spray formulation has a viscosity of at least about 100cP. In some embodiments, the pharmaceutical spray formulation has aviscosity of at most about 2,500 cP. In some embodiments, thepharmaceutical spray formulation has a viscosity of about 100 cP toabout 250 cP, about 100 cP to about 500 cP, about 100 cP to about 750cP, about 100 cP to about 1,000 cP, about 100 cP to about 1,250 cP,about 100 cP to about 1,500 cP, about 100 cP to about 1,750 cP, about100 cP to about 2,000 cP, about 100 cP to about 2,250 cP, about 100 cPto about 2,500 cP, about 250 cP to about 500 cP, about 250 cP to about750 cP, about 250 cP to about 1,000 cP, about 250 cP to about 1,250 cP,about 250 cP to about 1,500 cP, about 250 cP to about 1,750 cP, about250 cP to about 2,000 cP, about 250 cP to about 2,250 cP, about 250 cPto about 2,500 cP, about 500 cP to about 750 cP, about 500 cP to about1,000 cP, about 500 cP to about 1,250 cP, about 500 cP to about 1,500cP, about 500 cP to about 1,750 cP, about 500 cP to about 2,000 cP,about 500 cP to about 2,250 cP, about 500 cP to about 2,500 cP, about750 cP to about 1,000 cP, about 750 cP to about 1,250 cP, about 750 cPto about 1,500 cP, about 750 cP to about 1,750 cP, about 750 cP to about2,000 cP, about 750 cP to about 2,250 cP, about 750 cP to about 2,500cP, about 1,000 cP to about 1,250 cP, about 1,000 cP to about 1,500 cP,about 1,000 cP to about 1,750 cP, about 1,000 cP to about 2,000 cP,about 1,000 cP to about 2,250 cP, about 1,000 cP to about 2,500 cP,about 1,250 cP to about 1,500 cP, about 1,250 cP to about 1,750 cP,about 1,250 cP to about 2,000 cP, about 1,250 cP to about 2,250 cP,about 1,250 cP to about 2,500 cP, about 1,500 cP to about 1,750 cP,about 1,500 cP to about 2,000 cP, about 1,500 cP to about 2,250 cP,about 1,500 cP to about 2,500 cP, about 1,750 cP to about 2,000 cP,about 1,750 cP to about 2,250 cP, about 1,750 cP to about 2,500 cP,about 2,000 cP to about 2,250 cP, about 2,000 cP to about 2,500 cP, orabout 2,250 cP to about 2,500 cP. In some embodiments, thepharmaceutical spray formulation has a viscosity of about 100 cP, about250 cP, about 500 cP, about 750 cP, about 1,000 cP, about 1,250 cP,about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, or about2,500 cP.

In an aspect provided herein, the pharmaceutical spray formulationfurther comprises a viscosity modifier. In some embodiments, theviscosity modifier is polyethylene glycol, methylcellulose, orhypromellose.

In some embodiments, the pharmaceutical spray formulation furthercomprises polyethylene glycol. In some embodiments, the pharmaceuticalspray formulation further comprises from about 0.5% to about 50%polyethylene glycol.

In some embodiments, the pharmaceutical spray formulation furthercomprises methylcellulose. In some embodiments, the pharmaceutical sprayformulation further comprises from about 0.001% to about 5%methylcellulose.

In some embodiments, the pharmaceutical spray formulation furthercomprises hypromellose. In some embodiments, the pharmaceutical sprayformulation further comprises from about 0.001% to about 0.5%hypromellose. In some embodiments, the pharmaceutical spray formulationfurther comprises from about 0.05% to about 0.5% hypromellose. In someembodiments, the pharmaceutical spray formulation further comprises fromabout 0.05% to about 0.4% hypromellose. In some embodiments, thepharmaceutical spray formulation further comprises from about 0.05% toabout 0.3% hypromellose. In some embodiments, the pharmaceutical sprayformulation further comprises from about 0.05% to about 0.3%hypromellose. In some embodiments, the pharmaceutical spray formulationfurther comprises about 0.1% hypromellose.

Buffering Agents

In some embodiments, the pharmaceutical spray formulation comprises abuffering agent. In some embodiments, the buffering agent is citricacid, citrate, citric acid monohydrate, or any combination thereof. Insome embodiments, the buffering agent is sodium phosphate or sodiumcitrate.

In some embodiments, the pH of the pharmaceutical spray formulation isabout 3.5 to about 6.5. In some embodiments, the pH of thepharmaceutical spray formulation is about 3.5 to about 5.5. In someembodiments, the pH of the pharmaceutical spray formulation is about 3.5to about 4.5. In some embodiments, the pH of the pharmaceutical sprayformulation is about 4.0 to about 5.0. In some embodiments, the pH ofthe pharmaceutical spray formulation is about 4.5 to about 5.5. In someembodiments, the pH of the pharmaceutical spray formulation is about 4.5to about 6.5. In some embodiments, the pH of the pharmaceutical sprayformulation is about 5.5 to about 6.5. In some embodiments, the pH ofthe pharmaceutical spray formulation is about 3.5. In some embodiments,the pH of the pharmaceutical spray formulation is about 4. In someembodiments, the pH of the pharmaceutical spray formulation is about4.5. In some embodiments, the pH of the pharmaceutical spray formulationis about 4.7. In some embodiments, the pH of the pharmaceutical sprayformulation is about 5. In some embodiments, the pH of thepharmaceutical spray formulation is about 5.5. In some embodiments, thepH of the pharmaceutical spray formulation is about 6. In someembodiments, the pH of the pharmaceutical spray formulation is about6.5. In some embodiments, the pH of the pharmaceutical spray formulationis at least about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or about 6.0 and/or no morethan about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or about 6.0. In someembodiments, the pH of the pharmaceutical spray formulation is about4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or about 6.0.

In some embodiments, the pharmaceutical spray formulation has a pH ofabout 3.5 to about 7.5. In some embodiments, the pharmaceutical sprayformulation has a pH of at least about 3.5. In some embodiments, thepharmaceutical spray formulation has a pH of at most about 7.5. In someembodiments, the pharmaceutical spray formulation has a pH of about 3.5to about 4, about 3.5 to about 4.5, about 3.5 to about 5, about 3.5 toabout 5.5, about 3.5 to about 6, about 3.5 to about 6.5, about 3.5 toabout 7, about 3.5 to about 7.5, about 4 to about 4.5, about 4 to about5, about 4 to about 5.5, about 4 to about 6, about 4 to about 6.5, about4 to about 7, about 4 to about 7.5, about 4.5 to about 5, about 4.5 toabout 5.5, about 4.5 to about 6, about 4.5 to about 6.5, about 4.5 toabout 7, about 4.5 to about 7.5, about 5 to about 5.5, about 5 to about6, about 5 to about 6.5, about 5 to about 7, about 5 to about 7.5, about5.5 to about 6, about 5.5 to about 6.5, about 5.5 to about 7, about 5.5to about 7.5, about 6 to about 6.5, about 6 to about 7, about 6 to about7.5, about 6.5 to about 7, about 6.5 to about 7.5, or about 7 to about7.5. In some embodiments, the pharmaceutical spray formulation has a pHof about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about6.5, about 7, or about 7.5.

In some embodiments, the pH is controlled by the addition ofhydrochloric acid, citric acid, citrate, citric acid monohydrate, or acombination thereof. In some embodiments, the pH is controlled by theaddition of hydrochloric acid. In some embodiments, the pH is controlledby the addition of citric acid. In some embodiments, the pH iscontrolled by the addition of citrate. In some embodiments, the pH iscontrolled by the addition of citric acid monohydrate. In someembodiments, the pH is controlled by the addition of a combination ofhydrochloric acid and any of citric acid, citrate, of citric acidmonohydrate

In some embodiments, the pharmaceutical spray formulation comprises abuffering agent at a concentration of about 0.01% (w/w) to about 2%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises a buffering agent at a concentration of at least about 0.01%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises a buffering agent at a concentration of at most about 2%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises a buffering agent at a concentration of about 0.01% (w/w) toabout 0.1% (w/w), about 0.01% (w/w) to about 0.2% (w/w), about 0.01%(w/w) to about 0.3% (w/w), about 0.01% (w/w) to about 0.4% (w/w), about0.01% (w/w) to about 0.5% (w/w), about 0.01% (w/w) to about 0.6% (w/w),about 0.01% (w/w) to about 0.7% (w/w), about 0.01% (w/w) to about 0.8%(w/w), about 0.01% (w/w) to about 0.9% (w/w), about 0.01% (w/w) to about1% (w/w), about 0.01% (w/w) to about 2% (w/w), about 0.1% (w/w) to about0.2% (w/w), about 0.1% (w/w) to about 0.3% (w/w), about 0.1% (w/w) toabout 0.4% (w/w), about 0.1% (w/w) to about 0.5% (w/w), about 0.1% (w/w)to about 0.6% (w/w), about 0.1% (w/w) to about 0.7% (w/w), about 0.1%(w/w) to about 0.8% (w/w), about 0.1% (w/w) to about 0.9% (w/w), about0.1% (w/w) to about 1% (w/w), about 0.1% (w/w) to about 2% (w/w), about0.2% (w/w) to about 0.3% (w/w), about 0.2% (w/w) to about 0.4% (w/w),about 0.2% (w/w) to about 0.5% (w/w), about 0.2% (w/w) to about 0.6%(w/w), about 0.2% (w/w) to about 0.7% (w/w), about 0.2% (w/w) to about0.8% (w/w), about 0.2% (w/w) to about 0.9% (w/w), about 0.2% (w/w) toabout 1% (w/w), about 0.2% (w/w) to about 2% (w/w), about 0.3% (w/w) toabout 0.4% (w/w), about 0.3% (w/w) to about 0.5% (w/w), about 0.3% (w/w)to about 0.6% (w/w), about 0.3% (w/w) to about 0.7% (w/w), about 0.3%(w/w) to about 0.8% (w/w), about 0.3% (w/w) to about 0.9% (w/w), about0.3% (w/w) to about 1% (w/w), about 0.3% (w/w) to about 2% (w/w), about0.4% (w/w) to about 0.5% (w/w), about 0.4% (w/w) to about 0.6% (w/w),about 0.4% (w/w) to about 0.7% (w/w), about 0.4% (w/w) to about 0.8%(w/w), about 0.4% (w/w) to about 0.9% (w/w), about 0.4% (w/w) to about1% (w/w), about 0.4% (w/w) to about 2% (w/w), about 0.5% (w/w) to about0.6% (w/w), about 0.5% (w/w) to about 0.7% (w/w), about 0.5% (w/w) toabout 0.8% (w/w), about 0.5% (w/w) to about 0.9% (w/w), about 0.5% (w/w)to about 1% (w/w), about 0.5% (w/w) to about 2% (w/w), about 0.6% (w/w)to about 0.7% (w/w), about 0.6% (w/w) to about 0.8% (w/w), about 0.6%(w/w) to about 0.9% (w/w), about 0.6% (w/w) to about 1% (w/w), about0.6% (w/w) to about 2% (w/w), about 0.7% (w/w) to about 0.8% (w/w),about 0.7% (w/w) to about 0.9% (w/w), about 0.7% (w/w) to about 1%(w/w), about 0.7% (w/w) to about 2% (w/w), about 0.8% (w/w) to about0.9% (w/w), about 0.8% (w/w) to about 1% (w/w), about 0.8% (w/w) toabout 2% (w/w), about 0.9% (w/w) to about 1% (w/w), about 0.9% (w/w) toabout 2% (w/w), or about 1% (w/w) to about 2% (w/w). In someembodiments, the pharmaceutical spray formulation comprises a bufferingagent at a concentration of about 0.01% (w/w), about 0.1% (w/w), about0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about1% (w/w), or about 2% (w/w). In some embodiments, the buffering agent iscitric acid, for example, citric acid monohydrate.

In some embodiments, the pharmaceutical spray formulation furthercomprises trisodium citrate or citric acid monohydrate. In someembodiments, the pharmaceutical spray formulation further comprises fromabout 0.01% to about 2.0% trisodium citrate or citric acid monohydrate.In some embodiments, the pharmaceutical spray formulation furthercomprises from about 0.1% to about 2.0% trisodium citrate or citric acidmonohydrate. In some embodiments, the pharmaceutical spray formulationfurther comprises from about 0.1% to about 1.0% trisodium citrate orcitric acid monohydrate. In some embodiments, the pharmaceutical sprayformulation further comprises about 0.42% trisodium citrate or citricacid monohydrate.

Antioxidants

In an aspect provided herein, the pharmaceutical spray formulationcomprises an antioxidant. Antioxidants can reduce or mitigate oxidationof the active ingredient such as epinephrine. Examples of antioxidantsinclude sodium bisulfite, sodium metabisulfite, butylatedhydroxytoluene, and tocopherol. In some embodiments, the antioxidantcomprises sodium bisulfite or sodium metabisulfite. In some embodiments,the antioxidant comprises sodium bisulfite. In some embodiments, theantioxidant comprises sodium metabisulfite. In some embodiments, theantioxidant acts as a preservative. In some embodiments, the antioxidantis a preservative. In some embodiments, the preservative is sodiumbisulfite or sodium metabisulfite. In some embodiments, thepharmaceutical spray formulation comprises an antioxidant that reducesoxidation of the active ingredient such that the pharmaceutical sprayformulation that has no more than 1%, no more than 2%, no more than 3%,no more than 4%, no more than 5%, no more than 6%, no more than 7%, nomore than 8%, no more than 9%, no more than 10%, no more than 11%, nomore than 12%, no more than 13%, no more than 14%, no more than 15%impurities after storage at room temperature for at least 1 month, atleast 2 months, at least 3 months, at least 4 months, at least 5 months,at least 6 months, at least 7 months, at least 8 months, at least 9months, at least 10 months, at least 11 months, at least 12 months, atleast 13 months, at least 14 months, at least 15 months, at least 16months, at least 17 months, at least 18 months, at least 19 months, atleast 20 months, at least 21 months, at least 22 months, at least 23months, or at least 24 months. Room temperature can be from about 20degrees Celsius to about 25 degrees Celsius. In some embodiments, roomtemperature is about 20, 21, 22, 23, 24, or 25 degrees Celsius.

In some embodiments, the pharmaceutical spray formulation is a stableand/or pure formulation that minimizes oxidation of the activeingredient and/or the presence of impurities (w/w). In some embodiments,the pharmaceutical spray formulation has no more than 0.1%, no more than0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, no morethan 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, nomore than 1%, no more than 2%, no more than 3%, no more than 4%, no morethan 5%, no more than 6%, no more than 7%, no more than 8%, no more than9%, no more than 10%, no more than 11%, no more than 12%, no more than13%, no more than 14%, no more than 15% impurities after storage for atleast 1 month, at least 2 months, at least 3 months, at least 4 months,at least 5 months, at least 6 months, at least 7 months, at least 8months, at least 9 months, at least 10 months, at least 11 months, atleast 12 months, at least 13 months, at least 14 months, at least 15months, at least 16 months, at least 17 months, at least 18 months, atleast 19 months, at least 20 months, at least 21 months, at least 22months, at least 23 months, or at least 24 months. In some embodiments,the pharmaceutical spray formulation is stored at a temperature of atleast about 5 degrees Celsius, at least about 10 degrees Celsius, atleast about 20 degrees Celsius, at least about 25 degrees Celsius, atleast about 35 degrees Celsius, or at least about 40 degrees Celsiusand/or a temperature of no more than about 5 degrees Celsius, no morethan about 10 degrees Celsius, no more than about 20 degrees Celsius, nomore than about 25 degrees Celsius, no more than about 35 degreesCelsius, no more than about 40 degrees Celsius, or no more than about 45degrees Celsius. In some embodiments, the pharmaceutical sprayformulation is stored at a temperature of about 5 degrees Celsius, about10 degrees Celsius, about 20 degrees Celsius, about 25 degrees Celsius,about 35 degrees Celsius, or about 40 degrees Celsius. In someembodiments, the impurities content of the formulation is determinedrelative to an initial impurities content measured at 0 months (t=0). Insome embodiments, the impurities content of the formulation isdetermined as an absolute percentage.

In some embodiments, the impurities include one or more of epinephrinesulfonic acid, adrenochrome, norepinephrine, or adrenalone. In someembodiments, the pharmaceutical spray formulation has an epinephrinesulfonic acid content of no more than 0.1%, no more than 0.2%, no morethan 0.3%, no more than 0.4%, no more than 0.5%, no more than 0.6%, nomore than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%,no more than 2%, no more than 3%, no more than 4%, no more than 5%, nomore than 6%, no more than 7%, no more than 8%, or no more than 9%,after storage at about 5 degrees Celsius, about 25 degrees Celsius, orabout 40 degrees Celsius for at least 1 month, at least 2 months, atleast 3 months, at least 4 months, at least 5 months, at least 6 months,at least 7 months, at least 8 months, at least 9 months, at least 10months, at least 11 months, at least 12 months, at least 13 months, atleast 14 months, at least 15 months, at least 16 months, at least 17months, at least 18 months, at least 19 months, at least 20 months, atleast 21 months, at least 22 months, at least 23 months, or at least 24months.

In some embodiments, the pharmaceutical spray formulation has anadrenochrome content of no more than 0.1%, no more than 0.2%, no morethan 0.3%, no more than 0.4%, or no more than 0.5% after storage atabout 5 degrees Celsius, about 25 degrees Celsius, or about 40 degreesCelsius for at least 1 month, at least 2 months, at least 3 months, atleast 4 months, at least 5 months, at least 6 months, at least 7 months,at least 8 months, at least 9 months, at least 10 months, at least 11months, at least 12 months, at least 13 months, at least 14 months, atleast 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months, at least 23 months, or at least 24 months.

In some embodiments, the pharmaceutical spray formulation has anorepinephrine content of no more than 0.05%, no more than 0.1%, no morethan 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, nomore than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%,no more than 1%, no more than 2%, no more than 3%, or no more than 4%after storage at about 5 degrees Celsius, about 25 degrees Celsius, orabout 40 degrees Celsius for at least 1 month, at least 2 months, atleast 3 months, at least 4 months, at least 5 months, at least 6 months,at least 7 months, at least 8 months, at least 9 months, at least 10months, at least 11 months, at least 12 months, at least 13 months, atleast 14 months, at least 15 months, at least 16 months, at least 17months, at least 18 months, at least 19 months, at least 20 months, atleast 21 months, at least 22 months, at least 23 months, or at least 24months.

In some embodiments, the pharmaceutical spray formulation has anadrenalone content of no more than 0.05%, no more than 0.1%, no morethan 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, nomore than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%,no more than 1%, no more than 2%, or no more than 3% after storage atabout 5 degrees Celsius, about 25 degrees Celsius, or about 40 degreesCelsius for at least 1 month, at least 2 months, at least 3 months, atleast 4 months, at least 5 months, at least 6 months, at least 7 months,at least 8 months, at least 9 months, at least 10 months, at least 11months, at least 12 months, at least 13 months, at least 14 months, atleast 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months, at least 23 months, or at least 24 months.

In some embodiments, the pharmaceutical spray formulation comprises theL-isomer of epinephrine at an enantiomeric purity of at least 95%, 96%,97%, 98%, 99%, or 99.5%. In some embodiments, the pharmaceutical sprayformulation comprises the L-isomer of epinephrine at an enantiomericpurity of at least 95%, 96%, 97%, 98%, 99%, or 99.5% after storage atabout 5 degrees Celsius, about 25 degrees Celsius, or about 40 degreesCelsius for at least 1 month, at least 2 months, at least 3 months, atleast 4 months, at least 5 months, at least 6 months, at least 7 months,at least 8 months, at least 9 months, at least 10 months, at least 11months, at least 12 months, at least 13 months, at least 14 months, atleast 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months, at least 23 months, or at least 24 months.

In some embodiments, the pharmaceutical spray formulation comprises anantioxidant at a concentration of about 0.0001% (w/w) to about 0.5%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises an antioxidant at a concentration of at least about 0.0001%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises an antioxidant at a concentration of at most about 0.5% (w/w).In some embodiments, the pharmaceutical spray formulation comprises anantioxidant at a concentration of about 0.0001% (w/w) to about 0.001%(w/w), about 0.0001% (w/w) to about 0.01% (w/w), about 0.0001% (w/w) toabout 0.02% (w/w), about 0.0001% (w/w) to about 0.03% (w/w), about0.0001% (w/w) to about 0.04% (w/w), about 0.0001% (w/w) to about 0.05%(w/w), about 0.0001% (w/w) to about 0.1% (w/w), about 0.0001% (w/w) toabout 0.2% (w/w), about 0.0001% (w/w) to about 0.3% (w/w), about 0.0001%(w/w) to about 0.4% (w/w), about 0.0001% (w/w) to about 0.5% (w/w),about 0.001% (w/w) to about 0.01% (w/w), about 0.001% (w/w) to about0.02% (w/w), about 0.001% (w/w) to about 0.03% (w/w), about 0.001% (w/w)to about 0.04% (w/w), about 0.001% (w/w) to about 0.05% (w/w), about0.001% (w/w) to about 0.1% (w/w), about 0.001% (w/w) to about 0.2%(w/w), about 0.001% (w/w) to about 0.3% (w/w), about 0.001% (w/w) toabout 0.4% (w/w), about 0.001% (w/w) to about 0.5% (w/w), about 0.01%(w/w) to about 0.02% (w/w), about 0.01% (w/w) to about 0.03% (w/w),about 0.01% (w/w) to about 0.04% (w/w), about 0.01% (w/w) to about 0.05%(w/w), about 0.01% (w/w) to about 0.1% (w/w), about 0.01% (w/w) to about0.2% (w/w), about 0.01% (w/w) to about 0.3% (w/w), about 0.01% (w/w) toabout 0.4% (w/w), about 0.01% (w/w) to about 0.5% (w/w), about 0.02%(w/w) to about 0.03% (w/w), about 0.02% (w/w) to about 0.04% (w/w),about 0.02% (w/w) to about 0.05% (w/w), about 0.02% (w/w) to about 0.1%(w/w), about 0.02% (w/w) to about 0.2% (w/w), about 0.02% (w/w) to about0.3% (w/w), about 0.02% (w/w) to about 0.4% (w/w), about 0.02% (w/w) toabout 0.5% (w/w), about 0.03% (w/w) to about 0.04% (w/w), about 0.03%(w/w) to about 0.05% (w/w), about 0.03% (w/w) to about 0.1% (w/w), about0.03% (w/w) to about 0.2% (w/w), about 0.03% (w/w) to about 0.3% (w/w),about 0.03% (w/w) to about 0.4% (w/w), about 0.03% (w/w) to about 0.5%(w/w), about 0.04% (w/w) to about 0.05% (w/w), about 0.04% (w/w) toabout 0.1% (w/w), about 0.04% (w/w) to about 0.2% (w/w), about 0.04%(w/w) to about 0.3% (w/w), about 0.04% (w/w) to about 0.4% (w/w), about0.04% (w/w) to about 0.5% (w/w), about 0.05% (w/w) to about 0.1% (w/w),about 0.05% (w/w) to about 0.2% (w/w), about 0.05% (w/w) to about 0.3%(w/w), about 0.05% (w/w) to about 0.4% (w/w), about 0.05% (w/w) to about0.5% (w/w), about 0.1% (w/w) to about 0.2% (w/w), about 0.1% (w/w) toabout 0.3% (w/w), about 0.1% (w/w) to about 0.4% (w/w), about 0.1% (w/w)to about 0.5% (w/w), about 0.2% (w/w) to about 0.3% (w/w), about 0.2%(w/w) to about 0.4% (w/w), about 0.2% (w/w) to about 0.5% (w/w), about0.3% (w/w) to about 0.4% (w/w), about 0.3% (w/w) to about 0.5% (w/w), orabout 0.4% (w/w) to about 0.5% (w/w). In some embodiments, thepharmaceutical spray formulation comprises an antioxidant at aconcentration of about 0.0001% (w/w), about 0.001% (w/w), about 0.01%(w/w), about 0.02% (w/w), about 0.03% (w/w), about 0.04% (w/w), about0.05% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about0.4% (w/w), or about 0.5% (w/w).

In some embodiments, the pharmaceutical spray formulation comprisessodium bisulfite at a concentration of from about 0.0001% (w/w) to about0.05% (w/w) or sodium metabisulfite at a concentration of from about0.0001% (w/w) to about 0.1% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.1% (w/w). In some embodiments, the pharmaceutical spray formulationcomprises sodium bisulfite at a concentration of from about 0.001% (w/w)to about 0.05% (w/w) or sodium metabisulfite at a concentration of fromabout 0.001% (w/w) to about 0.1% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of from about 0.01% (w/w) to about 0.05% (w/w) or sodiummetabisulfite at a concentration of from about 0.01% (w/w) to about 0.1%(w/w).

In some embodiments, the pharmaceutical spray formulation comprisessodium bisulfite. In some embodiments, the pharmaceutical sprayformulation comprises sodium bisulfite at a concentration of from about0.0001% (w/w) to about 0.1% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of from about 0.001% (w/w) to about 0.05% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiumbisulfite at a concentration of from about 0.005% (w/w) to about 0.05%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises sodium bisulfite at a concentration of from about 0.001% (w/w)to about 0.05% (w/w). In some embodiments, the pharmaceutical sprayformulation comprises sodium bisulfite at a concentration of from about0.01% (w/w) to about 0.05% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.005% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.01% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.02% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.03% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.04% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium bisulfite at aconcentration of about 0.05% (w/w).

In some embodiments, the pharmaceutical spray formulation comprisessodium metabisulfite. In some embodiments, the pharmaceutical sprayformulation comprises sodium metabisulfite at a concentration of fromabout 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, thepharmaceutical spray formulation comprises sodium metabisulfite at aconcentration of from about 0.001% (w/w) to about 0.1% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of from about 0.005% (w/w) to about0.1% (w/w). In some embodiments, the pharmaceutical spray formulationcomprises sodium metabisulfite at a concentration of from about 0.01%(w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical sprayformulation comprises sodium metabisulfite at a concentration of about0.005% (w/w). In some embodiments, the pharmaceutical spray formulationcomprises sodium metabisulfite at a concentration of about 0.01% (w/w).In some embodiments, the pharmaceutical spray formulation comprisessodium metabisulfite at a concentration of about 0.02% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.03% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.04% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.05% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.06% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.07% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.08% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.09% (w/w). In someembodiments, the pharmaceutical spray formulation comprises sodiummetabisulfite at a concentration of about 0.1% (w/w).

In some embodiments, the pharmaceutical spray formulation comprises anantioxidant at a concentration of 0.01% (w/w) to 0.3% (w/w). In someembodiments, the antioxidant is sodium metabisulfite. In someembodiments, the pharmaceutical spray formulation comprises anantioxidant at a concentration of 0.01% (w/w) to 0.02% (w/w), 0.01%(w/w) to 0.03% (w/w), 0.01% (w/w) to 0.04% (w/w), 0.01% (w/w) to 0.05%(w/w), 0.01% (w/w) to 0.06% (w/w), 0.01% (w/w) to 0.07% (w/w), 0.01%(w/w) to 0.08% (w/w), 0.01% (w/w) to 0.09% (w/w), 0.01% (w/w) to 0.1%(w/w), 0.01% (w/w) to 0.2% (w/w), 0.01% (w/w) to 0.3% (w/w), 0.02% (w/w)to 0.03% (w/w), 0.02% (w/w) to 0.04% (w/w), 0.02% (w/w) to 0.05% (w/w),0.02% (w/w) to 0.06% (w/w), 0.02% (w/w) to 0.07% (w/w), 0.02% (w/w) to0.08% (w/w), 0.02% (w/w) to 0.09% (w/w), 0.02% (w/w) to 0.1% (w/w),0.02% (w/w) to 0.2% (w/w), 0.02% (w/w) to 0.3% (w/w), 0.03% (w/w) to0.04% (w/w), 0.03% (w/w) to 0.05% (w/w), 0.03% (w/w) to 0.06% (w/w),0.03% (w/w) to 0.07% (w/w), 0.03% (w/w) to 0.08% (w/w), 0.03% (w/w) to0.09% (w/w), 0.03% (w/w) to 0.1% (w/w), 0.03% (w/w) to 0.2% (w/w), 0.03%(w/w) to 0.3% (w/w), 0.04% (w/w) to 0.05% (w/w), 0.04% (w/w) to 0.06%(w/w), 0.04% (w/w) to 0.07% (w/w), 0.04% (w/w) to 0.08% (w/w), 0.04%(w/w) to 0.09% (w/w), 0.04% (w/w) to 0.1% (w/w), 0.04% (w/w) to 0.2%(w/w), 0.04% (w/w) to 0.3% (w/w), 0.05% (w/w) to 0.06% (w/w), 0.05%(w/w) to 0.07% (w/w), 0.05% (w/w) to 0.08% (w/w), 0.05% (w/w) to 0.09%(w/w), 0.05% (w/w) to 0.1% (w/w), 0.05% (w/w) to 0.2% (w/w), 0.05% (w/w)to 0.3% (w/w), 0.06% (w/w) to 0.07% (w/w), 0.06% (w/w) to 0.08% (w/w),0.06% (w/w) to 0.09% (w/w), 0.06% (w/w) to 0.1% (w/w), 0.06% (w/w) to0.2% (w/w), 0.06% (w/w) to 0.3% (w/w), 0.07% (w/w) to 0.08% (w/w), 0.07%(w/w) to 0.09% (w/w), 0.07% (w/w) to 0.1% (w/w), 0.07% (w/w) to 0.2%(w/w), 0.07% (w/w) to 0.3% (w/w), 0.08% (w/w) to 0.09% (w/w), 0.08%(w/w) to 0.1% (w/w), 0.08% (w/w) to 0.2% (w/w), 0.08% (w/w) to 0.3%(w/w), 0.09% (w/w) to 0.1% (w/w), 0.09% (w/w) to 0.2% (w/w), 0.09% (w/w)to 0.3% (w/w), 0.1% (w/w) to 0.2% (w/w), 0.1% (w/w) to 0.3% (w/w), or0.2% (w/w) to 0.3% (w/w). In some embodiments, the pharmaceutical sprayformulation comprises an antioxidant at a concentration of 0.01% (w/w),0.02% (w/w), 0.03% (w/w), 0.04% (w/w), 0.05% (w/w), 0.06% (w/w), 0.07%(w/w), 0.08% (w/w), 0.09% (w/w), 0.1% (w/w), 0.2% (w/w), or 0.3% (w/w).In some embodiments, the pharmaceutical spray formulation comprises anantioxidant at a concentration of at least 0.01% (w/w), 0.02% (w/w),0.03% (w/w), 0.04% (w/w), 0.05% (w/w), 0.06% (w/w), 0.07% (w/w), 0.08%(w/w), 0.09% (w/w), 0.1% (w/w), or 0.2% (w/w). In some embodiments, thepharmaceutical spray formulation comprises an antioxidant at aconcentration of at most 0.02% (w/w), 0.03% (w/w), 0.04% (w/w), 0.05%(w/w), 0.06% (w/w), 0.07% (w/w), 0.08% (w/w), 0.09% (w/w), 0.1% (w/w),0.2% (w/w), or 0.3% (w/w).

Preservatives

In an aspect provided herein, the pharmaceutical spray formulationcomprises a preservative. In some embodiments, the preservativecomprises a chelating agent. In some embodiments, the chelating agent isdisodium edetate (EDTA). In some embodiments, the pharmaceutical sprayformulation comprises disodium edetate. In some embodiments, thepharmaceutical spray formulation comprises disodium edetate at aconcentration of from about 0.0001% to about 0.01%. In some embodiments,the pharmaceutical spray formulation comprises disodium edetate at aconcentration of from about 0.0005% to about 0.01%. In some embodiments,the pharmaceutical spray formulation comprises disodium edetate at aconcentration of from about 0.001% to about 0.01%.

In some embodiments, the pharmaceutical spray formulation comprises achelating agent at a concentration of about 0.0001% to about 0.05%. Insome embodiments, the pharmaceutical spray formulation comprises achelating agent at a concentration of at least about 0.0001%. In someembodiments, the pharmaceutical spray formulation comprises a chelatingagent at a concentration of at most about 0.05%. In some embodiments,the pharmaceutical spray formulation comprises a chelating agent at aconcentration of about 0.0001% to about 0.0002%, about 0.0001% to about0.0003%, about 0.0001% to about 0.0004%, about 0.0001% to about 0.0005%,about 0.0001% to about 0.001%, about 0.0001% to about 0.005%, about0.0001% to about 0.01%, about 0.0001% to about 0.02%, about 0.0001% toabout 0.03%, about 0.0001% to about 0.04%, about 0.0001% to about 0.05%,about 0.0002% to about 0.0003%, about 0.0002% to about 0.0004%, about0.0002% to about 0.0005%, about 0.0002% to about 0.001%, about 0.0002%to about 0.005%, about 0.0002% to about 0.01%, about 0.0002% to about0.02%, about 0.0002% to about 0.03%, about 0.0002% to about 0.04%, about0.0002% to about 0.05%, about 0.0003% to about 0.0004%, about 0.0003% toabout 0.0005%, about 0.0003% to about 0.001%, about 0.0003% to about0.005%, about 0.0003% to about 0.01%, about 0.0003% to about 0.02%,about 0.0003% to about 0.03%, about 0.0003% to about 0.04%, about0.0003% to about 0.05%, about 0.0004% to about 0.0005%, about 0.0004% toabout 0.001%, about 0.0004% to about 0.005%, about 0.0004% to about0.01%, about 0.0004% to about 0.02%, about 0.0004% to about 0.03%, about0.0004% to about 0.04%, about 0.0004% to about 0.05%, about 0.0005% toabout 0.001%, about 0.0005% to about 0.005%, about 0.0005% to about0.01%, about 0.0005% to about 0.02%, about 0.0005% to about 0.03%, about0.0005% to about 0.04%, about 0.0005% to about 0.05%, about 0.001% toabout 0.005%, about 0.001% to about 0.01%, about 0.001% to about 0.02%,about 0.001% to about 0.03%, about 0.001% to about 0.04%, about 0.001%to about 0.05%, about 0.005% to about 0.01%, about 0.005% to about0.02%, about 0.005% to about 0.03%, about 0.005% to about 0.04%, about0.005% to about 0.05%, about 0.01% to about 0.02%, about 0.01% to about0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about0.02% to about 0.03%, about 0.02% to about 0.04%, about 0.02% to about0.05%, about 0.03% to about 0.04%, about 0.03% to about 0.05%, or about0.04% to about 0.05%. In some embodiments, the pharmaceutical sprayformulation comprises a chelating agent at a concentration of about0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about 0.0005%,about 0.001%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about0.04%, or about 0.05%.

In an aspect provided herein, the pharmaceutical spray formulationcomprises a preservative. Examples of preservatives include parabens,phenyl ethyl alcohol, benzalkonium chloride, EDTA, and benzoyl alcohol.In some embodiments, the preservative comprises an antimicrobialpreservative. In some embodiments, the antimicrobial preservative isbenzalkonium sodium or chlorobutanol. In some embodiments, theantimicrobial preservative is chlorobutanol. In some embodiments, thepharmaceutical spray formulation comprises benzalkonium sodium at aconcentration of from about 0.005% (w/v) to about 1% (w/v) orchlorobutanol at a concentration of from about 0.005% (w/v) to about 1%(w/v).

In some embodiments, the pharmaceutical spray formulation comprises anantimicrobial preservative at a concentration of about 0.01% (w/w) toabout 1% (w/w). In some embodiments, the antimicrobial preservative ischlorobutanol, for example, chlorobutanol hemihydrate. In someembodiments, the pharmaceutical spray formulation comprises anantimicrobial preservative at a concentration of at least about 0.01%(w/w). In some embodiments, the pharmaceutical spray formulationcomprises an antimicrobial preservative at a concentration of at mostabout 1% (w/w). In some embodiments, the pharmaceutical sprayformulation comprises an antimicrobial preservative at a concentrationof about 0.01% (w/w) to about 0.05% (w/w), about 0.01% (w/w) to about0.1% (w/w), about 0.01% (w/w) to about 0.2% (w/w), about 0.01% (w/w) toabout 0.3% (w/w), about 0.01% (w/w) to about 0.4% (w/w), about 0.01%(w/w) to about 0.5% (w/w), about 0.01% (w/w) to about 0.6% (w/w), about0.01% (w/w) to about 0.7% (w/w), about 0.01% (w/w) to about 0.8% (w/w),about 0.01% (w/w) to about 0.9% (w/w), about 0.01% (w/w) to about 1%(w/w), about 0.05% (w/w) to about 0.1% (w/w), about 0.05% (w/w) to about0.2% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) toabout 0.4% (w/w), about 0.05% (w/w) to about 0.5% (w/w), about 0.05%(w/w) to about 0.6% (w/w), about 0.05% (w/w) to about 0.7% (w/w), about0.05% (w/w) to about 0.8% (w/w), about 0.05% (w/w) to about 0.9% (w/w),about 0.05% (w/w) to about 1% (w/w), about 0.1% (w/w) to about 0.2%(w/w), about 0.1% (w/w) to about 0.3% (w/w), about 0.1% (w/w) to about0.4% (w/w), about 0.1% (w/w) to about 0.5% (w/w), about 0.1% (w/w) toabout 0.6% (w/w), about 0.1% (w/w) to about 0.7% (w/w), about 0.1% (w/w)to about 0.8% (w/w), about 0.1% (w/w) to about 0.9% (w/w), about 0.1%(w/w) to about 1% (w/w), about 0.2% (w/w) to about 0.3% (w/w), about0.2% (w/w) to about 0.4% (w/w), about 0.2% (w/w) to about 0.5% (w/w),about 0.2% (w/w) to about 0.6% (w/w), about 0.2% (w/w) to about 0.7%(w/w), about 0.2% (w/w) to about 0.8% (w/w), about 0.2% (w/w) to about0.9% (w/w), about 0.2% (w/w) to about 1% (w/w), about 0.3% (w/w) toabout 0.4% (w/w), about 0.3% (w/w) to about 0.5% (w/w), about 0.3% (w/w)to about 0.6% (w/w), about 0.3% (w/w) to about 0.7% (w/w), about 0.3%(w/w) to about 0.8% (w/w), about 0.3% (w/w) to about 0.9% (w/w), about0.3% (w/w) to about 1% (w/w), about 0.4% (w/w) to about 0.5% (w/w),about 0.4% (w/w) to about 0.6% (w/w), about 0.4% (w/w) to about 0.7%(w/w), about 0.4% (w/w) to about 0.8% (w/w), about 0.4% (w/w) to about0.9% (w/w), about 0.4% (w/w) to about 1% (w/w), about 0.5% (w/w) toabout 0.6% (w/w), about 0.5% (w/w) to about 0.7% (w/w), about 0.5% (w/w)to about 0.8% (w/w), about 0.5% (w/w) to about 0.9% (w/w), about 0.5%(w/w) to about 1% (w/w), about 0.6% (w/w) to about 0.7% (w/w), about0.6% (w/w) to about 0.8% (w/w), about 0.6% (w/w) to about 0.9% (w/w),about 0.6% (w/w) to about 1% (w/w), about 0.7% (w/w) to about 0.8%(w/w), about 0.7% (w/w) to about 0.9% (w/w), about 0.7% (w/w) to about1% (w/w), about 0.8% (w/w) to about 0.9% (w/w), about 0.8% (w/w) toabout 1% (w/w), or about 0.9% (w/w) to about 1% (w/w). In someembodiments, the pharmaceutical spray formulation comprises anantimicrobial preservative at a concentration of about 0.01% (w/w),about 0.05% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w),about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w),about 0.8% (w/w), about 0.9% (w/w), or about 1% (w/w).

In some embodiments, the pharmaceutical spray formulation comprisesbenzalkonium sodium. In some embodiments, the pharmaceutical sprayformulation comprises benzalkonium sodium at a concentration of fromabout 0.005% (w/v) to about 1% (w/v). In some embodiments, thepharmaceutical spray formulation comprises benzalkonium sodium at aconcentration of from about 0.01% (w/v) to about 1% (w/v). In someembodiments, the pharmaceutical spray formulation comprises benzalkoniumsodium at a concentration of from about 0.05% (w/v) to about 1% (w/v).In some embodiments, the pharmaceutical spray formulation comprisesbenzalkonium sodium at a concentration of from about 0.1% (w/v) to about1% (w/v).

In some embodiments, the pharmaceutical spray formulation compriseschlorobutanol. In some embodiments, the chlorobutanol is chlorobutanolhemihydrate. In some embodiments, the pharmaceutical spray formulationcomprises chlorobutanol at a concentration of from about 0.005% (w/v) toabout 1% (w/v) (or alternatively w/w). In some embodiments, thepharmaceutical spray formulation comprises chlorobutanol at aconcentration of from about 0.01% (w/v) to about 1% (w/v). In someembodiments, the pharmaceutical spray formulation compriseschlorobutanol at a concentration of from about 0.05% (w/v) to about 1%(w/v). In some embodiments, the pharmaceutical spray formulationcomprises chlorobutanol at a concentration of from about 0.1% (w/v) toabout 1% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises chlorobutanol at a concentration of from about0.1% (w/v) to about 0.5% (w/v). In some embodiments, the pharmaceuticalspray formulation comprises chlorobutanol at a concentration of about0.21% (w/v). In some embodiments, the pharmaceutical spray formulationcomprises chlorobutanol at a concentration of about 0.2% (w/v). In someembodiments, the pharmaceutical spray formulation compriseschlorobutanol at a concentration of about 0.5% (w/v).

Isotonicity Agents

Disclosed herein are various ingredients of the pharmaceutical sprayformulation. In some embodiments, the pharmaceutical spray formulationcomprises an isotonicity agent. In some embodiments, an isotonicityagent is sodium chloride. An isotonicity agent can be used to adjust thetonicity of the formulation. In some embodiments, the pharmaceuticalspray formulation is hypotonic. In some embodiments, the pharmaceuticalspray formulation is hypertonic. In some embodiments, the pharmaceuticalspray formulation is isotonic.

In some embodiments, the pharmaceutical spray formulation has anosmolality of about 550 mOsm/kg to about 800 mOsm/kg. In someembodiments, the pharmaceutical spray formulation has an osmolality ofabout 550 mOsm/kg to about 575 mOsm/kg, about 550 mOsm/kg to about 600mOsm/kg, about 550 mOsm/kg to about 625 mOsm/kg, about 550 mOsm/kg toabout 650 mOsm/kg, about 550 mOsm/kg to about 675 mOsm/kg, about 550mOsm/kg to about 700 mOsm/kg, about 550 mOsm/kg to about 725 mOsm/kg,about 550 mOsm/kg to about 750 mOsm/kg, about 550 mOsm/kg to about 775mOsm/kg, about 550 mOsm/kg to about 800 mOsm/kg, about 575 mOsm/kg toabout 600 mOsm/kg, about 575 mOsm/kg to about 625 mOsm/kg, about 575mOsm/kg to about 650 mOsm/kg, about 575 mOsm/kg to about 675 mOsm/kg,about 575 mOsm/kg to about 700 mOsm/kg, about 575 mOsm/kg to about 725mOsm/kg, about 575 mOsm/kg to about 750 mOsm/kg, about 575 mOsm/kg toabout 775 mOsm/kg, about 575 mOsm/kg to about 800 mOsm/kg, about 600mOsm/kg to about 625 mOsm/kg, about 600 mOsm/kg to about 650 mOsm/kg,about 600 mOsm/kg to about 675 mOsm/kg, about 600 mOsm/kg to about 700mOsm/kg, about 600 mOsm/kg to about 725 mOsm/kg, about 600 mOsm/kg toabout 750 mOsm/kg, about 600 mOsm/kg to about 775 mOsm/kg, about 600mOsm/kg to about 800 mOsm/kg, about 625 mOsm/kg to about 650 mOsm/kg,about 625 mOsm/kg to about 675 mOsm/kg, about 625 mOsm/kg to about 700mOsm/kg, about 625 mOsm/kg to about 725 mOsm/kg, about 625 mOsm/kg toabout 750 mOsm/kg, about 625 mOsm/kg to about 775 mOsm/kg, about 625mOsm/kg to about 800 mOsm/kg, about 650 mOsm/kg to about 675 mOsm/kg,about 650 mOsm/kg to about 700 mOsm/kg, about 650 mOsm/kg to about 725mOsm/kg, about 650 mOsm/kg to about 750 mOsm/kg, about 650 mOsm/kg toabout 775 mOsm/kg, about 650 mOsm/kg to about 800 mOsm/kg, about 675mOsm/kg to about 700 mOsm/kg, about 675 mOsm/kg to about 725 mOsm/kg,about 675 mOsm/kg to about 750 mOsm/kg, about 675 mOsm/kg to about 775mOsm/kg, about 675 mOsm/kg to about 800 mOsm/kg, about 700 mOsm/kg toabout 725 mOsm/kg, about 700 mOsm/kg to about 750 mOsm/kg, about 700mOsm/kg to about 775 mOsm/kg, about 700 mOsm/kg to about 800 mOsm/kg,about 725 mOsm/kg to about 750 mOsm/kg, about 725 mOsm/kg to about 775mOsm/kg, about 725 mOsm/kg to about 800 mOsm/kg, about 750 mOsm/kg toabout 775 mOsm/kg, about 750 mOsm/kg to about 800 mOsm/kg, or about 775mOsm/kg to about 800 mOsm/kg. In some embodiments, the pharmaceuticalspray formulation has an osmolality of about 550 mOsm/kg, about 575mOsm/kg, about 600 mOsm/kg, about 625 mOsm/kg, about 650 mOsm/kg, about675 mOsm/kg, about 700 mOsm/kg, about 725 mOsm/kg, about 750 mOsm/kg,about 775 mOsm/kg, or about 800 mOsm/kg. In some embodiments, thepharmaceutical spray formulation has an osmolality of at least about 550mOsm/kg, about 575 mOsm/kg, about 600 mOsm/kg, about 625 mOsm/kg, about650 mOsm/kg, about 675 mOsm/kg, about 700 mOsm/kg, about 725 mOsm/kg,about 750 mOsm/kg, or about 775 mOsm/kg. In some embodiments, thepharmaceutical spray formulation has an osmolality of at most about 575mOsm/kg, about 600 mOsm/kg, about 625 mOsm/kg, about 650 mOsm/kg, about675 mOsm/kg, about 700 mOsm/kg, about 725 mOsm/kg, about 750 mOsm/kg,about 775 mOsm/kg, or about 800 mOsm/kg.

In some embodiments, the pharmaceutical spray formulation comprises anisotonicity agent at a concentration of about 0.1% to about 4%. In someembodiments, the pharmaceutical spray formulation comprises anisotonicity agent at a concentration of at least about 0.1%. In someembodiments, the pharmaceutical spray formulation comprises anisotonicity agent at a concentration of at most about 4%. In someembodiments, the pharmaceutical spray formulation comprises anisotonicity agent at a concentration of about 0.1% to about 0.2%, about0.1% to about 0.4%, about 0.1% to about 0.5%, about 0.1% to about 0.6%,about 0.1% to about 0.8%, about 0.1% to about 1%, about 0.1% to about1.5%, about 0.1% to about 2%, about 0.1% to about 2.5%, about 0.1% toabout 3%, about 0.1% to about 4%, about 0.2% to about 0.4%, about 0.2%to about 0.5%, about 0.2% to about 0.6%, about 0.2% to about 0.8%, about0.2% to about 1%, about 0.2% to about 1.5%, about 0.2% to about 2%,about 0.2% to about 2.5%, about 0.2% to about 3%, about 0.2% to about4%, about 0.4% to about 0.5%, about 0.4% to about 0.6%, about 0.4% toabout 0.8%, about 0.4% to about 1%, about 0.4% to about 1.5%, about 0.4%to about 2%, about 0.4% to about 2.5%, about 0.4% to about 3%, about0.4% to about 4%, about 0.5% to about 0.6%, about 0.5% to about 0.8%,about 0.5% to about 1%, about 0.5% to about 1.5%, about 0.5% to about2%, about 0.5% to about 2.5%, about 0.5% to about 3%, about 0.5% toabout 4%, about 0.6% to about 0.8%, about 0.6% to about 1%, about 0.6%to about 1.5%, about 0.6% to about 2%, about 0.6% to about 2.5%, about0.6% to about 3%, about 0.6% to about 4%, about 0.8% to about 1%, about0.8% to about 1.5%, about 0.8% to about 2%, about 0.8% to about 2.5%,about 0.8% to about 3%, about 0.8% to about 4%, about 1% to about 1.5%,about 1% to about 2%, about 1% to about 2.5%, about 1% to about 3%,about 1% to about 4%, about 1.5% to about 2%, about 1.5% to about 2.5%,about 1.5% to about 3%, about 1.5% to about 4%, about 2% to about 2.5%,about 2% to about 3%, about 2% to about 4%, about 2.5% to about 3%,about 2.5% to about 4%, or about 3% to about 4%. In some embodiments,the pharmaceutical spray formulation comprises an isotonicity agent at aconcentration of about 0.1%, about 0.2%, about 0.4%, about 0.5%, about0.6%, about 0.8%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%,or about 4%.

In an aspect provided herein, the pharmaceutical spray formulationcomprises sodium chloride. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.1% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.1% to about 1%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.5% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about1% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about2% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about3% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about4% to about 5%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.1% to about 3%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.1% to about 2%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of from about0.1% to about 1%. In some embodiments, the pharmaceutical sprayformulation comprises sodium chloride at a concentration of about 0.4%.

In some embodiments, the pharmaceutical spray formulation is a stablepharmaceutical spray formulation that has no more than 1%, no more than2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%,no more than 7%, no more than 8%, no more than 9%, no more than 10%, nomore than 11%, no more than 12%, no more than 13%, no more than 14%, nomore than 15% impurities after storage at room temperature for at least1 month, at least 2 months, at least 3 months, at least 4 months, atleast 5 months, at least 6 months, at least 7 months, at least 8 months,at least 9 months, at least 10 months, at least 11 months, or at least12 months. In some embodiments, the pharmaceutical spray formulationcomprises one or more buffering agents and/or preservatives to improvestability of the active ingredient (e.g., reduce oxidation ordegradation of epinephrine) during storage.

Vasodilators

In an aspect provided herein, the pharmaceutical spray formulationfurther comprises a vasodilator. In some embodiments, the vasodilator isnitroprusside, phentolamine, or nifedipine.

In some embodiments, the pharmaceutical spray formulation furthercomprises nitroprusside. In some embodiments, the pharmaceutical sprayformulation further comprises from about 0.05 mg to about 5 mg ofnitroprusside. In some embodiments, the pharmaceutical spray formulationfurther comprises from about 0.1 mg to about 5 mg of nitroprusside. Insome embodiments, the pharmaceutical spray formulation further comprisesfrom about 0.5 mg to about 5 mg of nitroprusside. In some embodiments,the pharmaceutical spray formulation further comprises from about 1 mgto about 5 mg of nitroprusside. In some embodiments, the pharmaceuticalspray formulation further comprises from about 1 mg to about 4 mg ofnitroprusside. In some embodiments, the pharmaceutical spray formulationfurther comprises nitroprusside. In some embodiments, the pharmaceuticalspray formulation further comprises from about 0.05 mg to about 3 mg ofnitroprusside. In some embodiments, the pharmaceutical spray formulationfurther comprises nitroprusside. In some embodiments, the pharmaceuticalspray formulation further comprises from about 0.5 mg to about 3 mg ofnitroprusside. In some embodiments, the pharmaceutical spray formulationfurther comprises nitroprusside. In some embodiments, the pharmaceuticalspray formulation further comprises from about 0.5 mg to about 2 mg ofnitroprusside.

In some embodiments, the pharmaceutical spray formulation furthercomprises phentolamine. In some embodiments, the pharmaceutical sprayformulation further comprises from about 1 mg to about 50 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 1 mg to about 40 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 1 mg to about 30 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 1 mg to about 20 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 1 mg to about 10 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 5 mg to about 50 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 50 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 20 mg to about 50 mg ofphentolamine. In some embodiments, the pharmaceutical spray formulationfurther comprises phentolamine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 20 mg to about 40 mg ofphentolamine.

In some embodiments, the pharmaceutical spray formulation furthercomprises nifedipine. In some embodiments, the pharmaceutical sprayformulation further comprises from about 10 mg to about 500 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 450 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 400 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 350 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 300 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 250 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 200 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 150 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 100 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 75 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 50 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 40 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 10 mg to about 30 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 50 mg to about 500 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 100 mg to about 500 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 100 mg to about 400 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 100 mg to about 350 mg ofnifedipine. In some embodiments, the pharmaceutical spray formulationfurther comprises nifedipine. In some embodiments, the pharmaceuticalspray formulation further comprises from about 100 mg to about 300 mg ofnifedipine.

Absorption Enhancers

In an aspect provided herein, the pharmaceutical spray formulationcomprises an absorption enhancer. In some embodiments, the absorptionenhancer comprises caprylic acid, oleic acid, polysorbate 80, menthol,EDTA, sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate,citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryloleate, L-lysine, diethylene glycol monoethyl ether, α- β- orγ-cyclodextrin, hydroxypropyl β-cyclodextrin, phosphatidylcholine, orcombinations thereof. Absorption enhancers can improve thepharmacokinetics of the active ingredient(s) of the pharmaceutical sprayformulation. In some embodiments, the improved pharmacokinetics includesone or more of C_(max), T_(max), and AUC. In some cases, the absorptionenhancer comprises diethylene glycol monoethyl ether. In some cases, useof absorption enhancers can reduce T_(max). Absorption enhancers may beused to increase the AUC of the active ingredient.

In some embodiments, the pharmaceutical spray formulation comprises anabsorption enhancer at a concentration of about 0.1% to about 2%. Insome embodiments, the pharmaceutical spray formulation comprises anabsorption enhancer at a concentration of at least about 0.1%. In someembodiments, the pharmaceutical spray formulation comprises anabsorption enhancer at a concentration of at most about 2%. In someembodiments, the pharmaceutical spray formulation comprises anabsorption enhancer at a concentration of about 0.1% to about 0.2%,about 0.1% to about 0.3%, about 0.1% to about 0.4%, about 0.1% to about0.5%, about 0.1% to about 0.6%, about 0.1% to about 0.7%, about 0.1% toabout 0.8%, about 0.1% to about 0.9%, about 0.1% to about 1%, about 0.1%to about 1.5%, about 0.1% to about 2%, about 0.2% to about 0.3%, about0.2% to about 0.4%, about 0.2% to about 0.5%, about 0.2% to about 0.6%,about 0.2% to about 0.7%, about 0.2% to about 0.8%, about 0.2% to about0.9%, about 0.2% to about 1%, about 0.2% to about 1.5%, about 0.2% toabout 2%, about 0.3% to about 0.4%, about 0.3% to about 0.5%, about 0.3%to about 0.6%, about 0.3% to about 0.7%, about 0.3% to about 0.8%, about0.3% to about 0.9%, about 0.3% to about 1%, about 0.3% to about 1.5%,about 0.3% to about 2%, about 0.4% to about 0.5%, about 0.4% to about0.6%, about 0.4% to about 0.7%, about 0.4% to about 0.8%, about 0.4% toabout 0.9%, about 0.4% to about 1%, about 0.4% to about 1.5%, about 0.4%to about 2%, about 0.5% to about 0.6%, about 0.5% to about 0.7%, about0.5% to about 0.8%, about 0.5% to about 0.9%, about 0.5% to about 1%,about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.6% to about0.7%, about 0.6% to about 0.8%, about 0.6% to about 0.9%, about 0.6% toabout 1%, about 0.6% to about 1.5%, about 0.6% to about 2%, about 0.7%to about 0.8%, about 0.7% to about 0.9%, about 0.7% to about 1%, about0.7% to about 1.5%, about 0.7% to about 2%, about 0.8% to about 0.9%,about 0.8% to about 1%, about 0.8% to about 1.5%, about 0.8% to about2%, about 0.9% to about 1%, about 0.9% to about 1.5%, about 0.9% toabout 2%, about 1% to about 1.5%, about 1% to about 2%, or about 1.5% toabout 2%. In some embodiments, the pharmaceutical spray formulationcomprises an absorption enhancer at a concentration of about 0.1%, about0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about0.8%, about 0.9%, about 1%, about 1.5%, or about 2%.

In some embodiments, the pharmaceutical spray formulation comprises anabsorption enhancer at a concentration of at least about 0.1%, at leastabout 0.2%, at least about 0.3%, at least about 0.4%, at least about0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, atleast about 0.9%, at least about 1.0%, at least about 1.1%, at leastabout 1.2%, at least about 1.3%, at least about 1.4%, at least about1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, atleast about 1.9%, at least about 2.0%, at least about 2.5%, at leastabout 3.0%, at least about 4.0%, at least about 5.0%, and/or no morethan about 0.1%, no more than about 0.2%, no more than about 0.3%, nomore than about 0.4%, no more than about 0.5%, no more than about 0.6%,no more than about 0.7%, no more than about 0.8%, no more than about0.9%, no more than about 1.0%, no more than about 1.1%, no more thanabout 1.2%, no more than about 1.3%, no more than about 1.4%, no morethan about 1.5%, no more than about 1.6%, no more than about 1.7%, nomore than about 1.8%, no more than about 1.9%, no more than about 2.0%,no more than about 2.5%, no more than about 3.0%, no more than about4.0%, or no more than about 5.0%. In some embodiments, the absorptionenhancer is diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises 1% diethylene glycolmonoethyl ether.

In an aspect provided herein, the pharmaceutical spray formulationfurther comprises a permeability enhancer or absorption enhancer.

In an aspect provided herein, the pharmaceutical spray formulationfurther comprises diethylene glycol monoethyl ether. In someembodiments, the pharmaceutical spray formulation further comprisesdiethylene glycol monoethyl ether at a concentration of from about 0.05%to about 15%. In some embodiments, the pharmaceutical spray formulationfurther comprises diethylene glycol monoethyl ether at a concentrationof from about 0.5% to about 10%. In some embodiments, the pharmaceuticalspray formulation further comprises diethylene glycol monoethyl ether ata concentration of from about 0.5% to about 5%. In some embodiments, thepharmaceutical spray formulation further comprises diethylene glycolmonoethyl ether at a concentration of from about 0.5% to about 4%. Insome embodiments, the pharmaceutical spray formulation further comprisesdiethylene glycol monoethyl ether at a concentration of from about 0.5%to about 3%. In some embodiments, the pharmaceutical spray formulationfurther comprises diethylene glycol monoethyl ether at a concentrationof from about 0.5% to about 2%. In some embodiments, the pharmaceuticalspray formulation further comprises diethylene glycol monoethyl ether ata concentration of about 1%.

Formulations

In some aspects, disclosed herein are pharmaceutical spray formulationscomprising an active ingredient or pharmaceutically acceptable saltthereof, and one or more excipients, vehicles, emulsifiers, stabilizingagents, preservatives, mucosal adhesives, antibacterial agents, buffers,and/or other additives. In some embodiments, the pharmaceutical sprayformulation comprises at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, or at leasteight of an excipient, vehicle, emulsifier, stabilizing agent,preservative, mucosal adhesive, antibacterial agent, buffer, and/orother additive. In some embodiments, the pharmaceutical sprayformulation comprises at least one, at least two, at least three, atleast four, at least five, or at least six of an antioxidant, achelating agent, an antimicrobial preservative, a viscosity modifier, abuffering agent, or an absorption enhancer. In some embodiments, thepharmaceutical spray formulation comprises at least one preservativethat is an antioxidant, a chelating agent, an antimicrobialpreservative, or any combination thereof. In some embodiments, thepharmaceutical spray formulation comprises an active ingredient (e.g.,epinephrine), or a pharmaceutically acceptable salt thereof, and atleast one, at least two, at least three, at least four, at least five,or at least six of an antioxidant, an isotonicity agent, a viscositymodifier, a buffering agent, an absorption enhancer, or an antimicrobialpreservative. In some embodiments, the pharmaceutical spray formulationcomprises an active ingredient (e.g., epinephrine), or apharmaceutically acceptable salt thereof, an antioxidant, an isotonicityagent, a viscosity modifier, a buffering agent, an absorption enhancer,and an antimicrobial preservative.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 5% of an isotonicity agent,from about 0.001% to about 0.5% of a viscosity modifier, from about0.01% to about 2.0% of a buffering agent, and from about 0.05% to about15% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant,from about 0.1% to about 5% of an isotonicity agent, from about 0.001%to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of abuffering agent, and from about 0.05% to about 15% of an absorptionenhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant,from about 0.1% to about 1% of an isotonicity agent, from about 0.01% toabout 0.2% of a viscosity modifier, from about 0.1% to about 1% of abuffering agent, and from about 0.1% to about 5% of an absorptionenhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant,from about 0.1% to about 5% of an isotonicity agent, from about 0.001%to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of abuffering agent, and from about 0.05% to about 15% of an absorptionenhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant,from about 0.1% to about 1% of an isotonicity agent, from about 0.01% toabout 0.2% of a viscosity modifier, from about 0.1% to about 1% of abuffering agent, and from about 0.1% to about 5% of an absorptionenhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 5% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 1.0% of an isotonicity agent,from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1%to about 1.0% of a buffering agent, and from about 0.1% to about 2.0% ofan absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 5% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 1.0% of an isotonicity agent,from about 0.05% to about 0.5% of a viscosity modifier, from about 0.1%to about 1.0% of a buffering agent, and from about 0.5% to about 5% ofan absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2.4% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of abuffering agent, and about 1% of an absorption enhancer. In someembodiments, the pharmaceutical spray formulation comprises about 10%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 20% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 5% of an isotonicity agent,from about 0.001% to about 0.5% of a viscosity modifier, from about0.01% to about 2% of a buffering agent, and from about 0.05% to about15% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 5% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 1% of an isotonicity agent,from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1%to about 1% of a buffering agent citrate, and from about 0.1% to about5% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 5% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofan antioxidant, from about 0.1% to about 1% of an isotonicity agent,from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1%to about 1% of a buffering agent, and from about 0.1% to about 5% of anabsorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 10% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation comprisesabout 20% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, and about 1% of an absorption enhancer.

In some embodiments, the pharmaceutical spray formulation furthercomprises an antimicrobial preservative at a concentration of from about0.05% (w/v) to about 1% (w/v).

In some embodiments, the pharmaceutical spray formulation comprisesabout 2.4% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of abuffering agent, about 1% of an absorption enhancer, and about 0.2% anantimicrobial preservative.

In some embodiments, the pharmaceutical spray formulation comprisesabout 4.6% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of abuffering agent, about 1% of an absorption enhancer, and about 0.2% anantimicrobial preservative.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, about 1% of an absorption enhancer, and about 0.21% anantimicrobial preservative

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of an antioxidant, about 0.4% of anisotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of abuffering agent, about 1% of an absorption enhancer, and about 0.21% anantimicrobial preservative.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 5% sodium chloride, fromabout 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0%trisodium citrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 5% sodium chloride, from about0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citricacid monohydrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 1% sodium chloride, from about0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citricacid monohydrate, and from about 0.1% to about 5% diethylene glycolmonoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 5% sodium chloride, from about0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citricacid monohydrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 1% sodium chloride, from about0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citricacid monohydrate, and from about 0.1% to about 5% diethylene glycolmonoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 5% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 1.0% sodium chloride,from about 0.01% to about 0.2% hypromellose, from about 0.1% to about1.0% trisodium citrate, and from about 0.1% to about 2.0% diethyleneglycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 5% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 1.0% sodium chloride,from about 0.05% to about 0.5% hypromellose, from about 0.1% to about1.0% trisodium citrate, and from about 0.5% to about 5% diethyleneglycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2.4% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, andabout 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, andabout 1% diethylene glycol monoethyl ether. In some embodiments, thepharmaceutical spray formulation comprises about 10% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) ofsodium metabisulfite, about 0.4% sodium chloride, about 0.1%hypromellose, about 0.7% trisodium citrate, and about 1% diethyleneglycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 20% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, andabout 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 5% sodium chloride, fromabout 0.001% to about 0.5% hypromellose, from about 0.01% to about 2%citric acid monohydrate, and from about 0.05% to about 15% diethyleneglycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 1% to about 5% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 1% sodium chloride, fromabout 0.01% to about 0.2% hypromellose, from about 0.1% to about 1%citric acid monohydrate citrate, and from about 0.1% to about 5%diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprises fromabout 5% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 1% sodium chloride, fromabout 0.01% to about 0.2% hypromellose, from about 0.1% to about 1%citric acid monohydrate, and from about 0.1% to about 5% diethyleneglycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 10% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation comprisesabout 20% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray formulation furthercomprises chlorobutanol at a concentration of from about 0.05% (w/v) toabout 1% (w/v).

In some embodiments, the pharmaceutical spray formulation comprisesabout 2.4% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about1% diethylene glycol monoethyl ether, and about 0.2% chlorobutanol.

In some embodiments, the pharmaceutical spray formulation comprisesabout 4.6% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about1% diethylene glycol monoethyl ether, and about 0.2% chlorobutanol.

In some embodiments, the pharmaceutical spray formulation comprisesabout 2% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,about 1% diethylene glycol monoethyl ether, and about 0.21%chlorobutanol

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate,about 1% diethylene glycol monoethyl ether, and about 0.21%chlorobutanol.

In some embodiments, the pharmaceutical spray formulation comprisesabout 5% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

In some embodiments, the pharmaceutical spray formulation comprisesabout 4% w/w of epinephrine, or a pharmaceutically acceptable saltthereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodiumchloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

Intranasal Delivery

In an aspect provided herein, the pharmaceutical spray formulation has adroplet size of D50 of from about 10 microns to about 100 microns. Insome embodiments, the pharmaceutical spray formulation has a dropletsize of D50 of from about 10 microns to about 80 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of from about 10 microns to about 60 microns. In some embodiments,the pharmaceutical spray formulation has a droplet size of D50 of fromabout 10 microns to about 40 microns. In some embodiments, thepharmaceutical spray formulation has a droplet size of D50 of from about10 microns to about 20 microns. In some embodiments, the pharmaceuticalspray formulation has a droplet size of D50 of about 10 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of about 20 microns. In some embodiments, the pharmaceutical sprayformulation has a droplet size of D50 of about 30 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of about 40 microns. In some embodiments, the pharmaceutical sprayformulation has a droplet size of D50 of about 50 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of about 60 microns. In some embodiments, the pharmaceutical sprayformulation has a droplet size of D50 of about 70 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of about 80 microns. In some embodiments, the pharmaceutical sprayformulation has a droplet size of D50 of about 90 microns. In someembodiments, the pharmaceutical spray formulation has a droplet size ofD50 of about 100 microns.

In some embodiments, the pharmaceutical spray formulation is deliveredas one or more sprays having a droplet size distribution characterizedby certain D10, D50, or D90 values. In some embodiments, thepharmaceutical spray formulation is delivered as a spray with a D10droplet size of about 15 microns to about 30 microns. In someembodiments, the pharmaceutical spray formulation is delivered as aspray with a D10 droplet size of about 15 microns to about 16 microns,about 15 microns to about 17 microns, about 15 microns to about 18microns, about 15 microns to about 19 microns, about 15 microns to about20 microns, about 15 microns to about 21 microns, about 15 microns toabout 22 microns, about 15 microns to about 25 microns, about 15 micronsto about 30 microns, about 16 microns to about 17 microns, about 16microns to about 18 microns, about 16 microns to about 19 microns, about16 microns to about 20 microns, about 16 microns to about 21 microns,about 16 microns to about 22 microns, about 16 microns to about 25microns, about 16 microns to about 30 microns, about 17 microns to about18 microns, about 17 microns to about 19 microns, about 17 microns toabout 20 microns, about 17 microns to about 21 microns, about 17 micronsto about 22 microns, about 17 microns to about 25 microns, about 17microns to about 30 microns, about 18 microns to about 19 microns, about18 microns to about 20 microns, about 18 microns to about 21 microns,about 18 microns to about 22 microns, about 18 microns to about 25microns, about 18 microns to about 30 microns, about 19 microns to about20 microns, about 19 microns to about 21 microns, about 19 microns toabout 22 microns, about 19 microns to about 25 microns, about 19 micronsto about 30 microns, about 20 microns to about 21 microns, about 20microns to about 22 microns, about 20 microns to about 25 microns, about20 microns to about 30 microns, about 21 microns to about 22 microns,about 21 microns to about 25 microns, about 21 microns to about 30microns, about 22 microns to about 25 microns, about 22 microns to about30 microns, or about 25 microns to about 30 microns. In someembodiments, the pharmaceutical spray formulation is delivered as aspray with a D10 droplet size of about 15 microns, about 16 microns,about 17 microns, about 18 microns, about 19 microns, about 20 microns,about 21 microns, about 22 microns, about 25 microns, or about 30microns. In some embodiments, the pharmaceutical spray formulation isdelivered as a spray with a D10 droplet size of at least about 15microns, about 16 microns, about 17 microns, about 18 microns, about 19microns, about 20 microns, about 21 microns, about 22 microns, or about25 microns. In some embodiments, the pharmaceutical spray formulation isdelivered as a spray with a D10 droplet size of at most about 16microns, about 17 microns, about 18 microns, about 19 microns, about 20microns, about 21 microns, about 22 microns, about 25 microns, or about30 microns.

In some embodiments, the pharmaceutical spray formulation is deliveredas a spray with a D50 droplet size of about 35 microns to about 80microns. In some embodiments, the pharmaceutical spray formulation isdelivered as a spray with a D50 droplet size of about 35 microns toabout 40 microns, about 35 microns to about 42 microns, about 35 micronsto about 44 microns, about 35 microns to about 46 microns, about 35microns to about 48 microns, about 35 microns to about 50 microns, about35 microns to about 52 microns, about 35 microns to about 55 microns,about 35 microns to about 60 microns, about 35 microns to about 70microns, about 35 microns to about 80 microns, about 40 microns to about42 microns, about 40 microns to about 44 microns, about 40 microns toabout 46 microns, about 40 microns to about 48 microns, about 40 micronsto about 50 microns, about 40 microns to about 52 microns, about 40microns to about 55 microns, about 40 microns to about 60 microns, about40 microns to about 70 microns, about 40 microns to about 80 microns,about 42 microns to about 44 microns, about 42 microns to about 46microns, about 42 microns to about 48 microns, about 42 microns to about50 microns, about 42 microns to about 52 microns, about 42 microns toabout 55 microns, about 42 microns to about 60 microns, about 42 micronsto about 70 microns, about 42 microns to about 80 microns, about 44microns to about 46 microns, about 44 microns to about 48 microns, about44 microns to about 50 microns, about 44 microns to about 52 microns,about 44 microns to about 55 microns, about 44 microns to about 60microns, about 44 microns to about 70 microns, about 44 microns to about80 microns, about 46 microns to about 48 microns, about 46 microns toabout 50 microns, about 46 microns to about 52 microns, about 46 micronsto about 55 microns, about 46 microns to about 60 microns, about 46microns to about 70 microns, about 46 microns to about 80 microns, about48 microns to about 50 microns, about 48 microns to about 52 microns,about 48 microns to about 55 microns, about 48 microns to about 60microns, about 48 microns to about 70 microns, about 48 microns to about80 microns, about 50 microns to about 52 microns, about 50 microns toabout 55 microns, about 50 microns to about 60 microns, about 50 micronsto about 70 microns, about 50 microns to about 80 microns, about 52microns to about 55 microns, about 52 microns to about 60 microns, about52 microns to about 70 microns, about 52 microns to about 80 microns,about 55 microns to about 60 microns, about 55 microns to about 70microns, about 55 microns to about 80 microns, about 60 microns to about70 microns, about 60 microns to about 80 microns, or about 70 microns toabout 80 microns. In some embodiments, the pharmaceutical sprayformulation is delivered as a spray with a D50 droplet size of about 35microns, about 40 microns, about 42 microns, about 44 microns, about 46microns, about 48 microns, about 50 microns, about 52 microns, about 55microns, about 60 microns, about 70 microns, or about 80 microns. Insome embodiments, the pharmaceutical spray formulation is delivered as aspray with a D50 droplet size of at least about 35 microns, about 40microns, about 42 microns, about 44 microns, about 46 microns, about 48microns, about 50 microns, about 52 microns, about 55 microns, about 60microns, or about 70 microns. In some embodiments, the pharmaceuticalspray formulation is delivered as a spray with a D50 droplet size of atmost about 40 microns, about 42 microns, about 44 microns, about 46microns, about 48 microns, about 50 microns, about 52 microns, about 55microns, about 60 microns, about 70 microns, or about 80 microns.

In some embodiments, the pharmaceutical spray formulation is deliveredas a spray with a D90 droplet size of about 80 microns to about 180microns. In some embodiments, the pharmaceutical spray formulation isdelivered as a spray with a D90 droplet size of about 80 microns toabout 90 microns, about 80 microns to about 100 microns, about 80microns to about 110 microns, about 80 microns to about 115 microns,about 80 microns to about 120 microns, about 80 microns to about 130microns, about 80 microns to about 140 microns, about 80 microns toabout 150 microns, about 80 microns to about 160 microns, about 80microns to about 170 microns, about 80 microns to about 180 microns,about 90 microns to about 100 microns, about 90 microns to about 110microns, about 90 microns to about 115 microns, about 90 microns toabout 120 microns, about 90 microns to about 130 microns, about 90microns to about 140 microns, about 90 microns to about 150 microns,about 90 microns to about 160 microns, about 90 microns to about 170microns, about 90 microns to about 180 microns, about 100 microns toabout 110 microns, about 100 microns to about 115 microns, about 100microns to about 120 microns, about 100 microns to about 130 microns,about 100 microns to about 140 microns, about 100 microns to about 150microns, about 100 microns to about 160 microns, about 100 microns toabout 170 microns, about 100 microns to about 180 microns, about 110microns to about 115 microns, about 110 microns to about 120 microns,about 110 microns to about 130 microns, about 110 microns to about 140microns, about 110 microns to about 150 microns, about 110 microns toabout 160 microns, about 110 microns to about 170 microns, about 110microns to about 180 microns, about 115 microns to about 120 microns,about 115 microns to about 130 microns, about 115 microns to about 140microns, about 115 microns to about 150 microns, about 115 microns toabout 160 microns, about 115 microns to about 170 microns, about 115microns to about 180 microns, about 120 microns to about 130 microns,about 120 microns to about 140 microns, about 120 microns to about 150microns, about 120 microns to about 160 microns, about 120 microns toabout 170 microns, about 120 microns to about 180 microns, about 130microns to about 140 microns, about 130 microns to about 150 microns,about 130 microns to about 160 microns, about 130 microns to about 170microns, about 130 microns to about 180 microns, about 140 microns toabout 150 microns, about 140 microns to about 160 microns, about 140microns to about 170 microns, about 140 microns to about 180 microns,about 150 microns to about 160 microns, about 150 microns to about 170microns, about 150 microns to about 180 microns, about 160 microns toabout 170 microns, about 160 microns to about 180 microns, or about 170microns to about 180 microns. In some embodiments, the pharmaceuticalspray formulation is delivered as a spray with a D90 droplet size ofabout 80 microns, about 90 microns, about 100 microns, about 110microns, about 115 microns, about 120 microns, about 130 microns, about140 microns, about 150 microns, about 160 microns, about 170 microns, orabout 180 microns. In some embodiments, the pharmaceutical sprayformulation is delivered as a spray with a D90 droplet size of at leastabout 80 microns, about 90 microns, about 100 microns, about 110microns, about 115 microns, about 120 microns, about 130 microns, about140 microns, about 150 microns, about 160 microns, or about 170 microns.In some embodiments, the pharmaceutical spray formulation is deliveredas a spray with a D90 droplet size of at most about 90 microns, about100 microns, about 110 microns, about 115 microns, about 120 microns,about 130 microns, about 140 microns, about 150 microns, about 160microns, about 170 microns, or about 180 microns.

In some embodiments, the pharmaceutical spray formulation is deliveredas a spray that has a % volume <10 microns of about 0.2% to about 5%. Insome embodiments, the pharmaceutical spray formulation is delivered as aspray that has a % volume <10 microns of about 0.2% to about 0.4%, about0.2% to about 0.6%, about 0.2% to about 0.8%, about 0.2% to about 1%,about 0.2% to about 1.5%, about 0.2% to about 2%, about 0.2% to about3%, about 0.2% to about 4%, about 0.2% to about 5%, about 0.4% to about0.6%, about 0.4% to about 0.8%, about 0.4% to about 1%, about 0.4% toabout 1.5%, about 0.4% to about 2%, about 0.4% to about 3%, about 0.4%to about 4%, about 0.4% to about 5%, about 0.6% to about 0.8%, about0.6% to about 1%, about 0.6% to about 1.5%, about 0.6% to about 2%,about 0.6% to about 3%, about 0.6% to about 4%, about 0.6% to about 5%,about 0.8% to about 1%, about 0.8% to about 1.5%, about 0.8% to about2%, about 0.8% to about 3%, about 0.8% to about 4%, about 0.8% to about5%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%,about 1% to about 4%, about 1% to about 5%, about 1.5% to about 2%,about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%,about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about3% to about 4%, about 3% to about 5%, or about 4% to about 5%. In someembodiments, the pharmaceutical spray formulation is delivered as aspray that has a % volume <10 microns of about 0.2%, about 0.4%, about0.6%, about 0.8%, about 1%, about 1.5%, about 2%, about 3%, about 4%, orabout 5%. In some embodiments, the pharmaceutical spray formulation isdelivered as a spray that has a % volume <10 microns of at least about0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.5%, about2%, about 3%, or about 4%. In some embodiments, the pharmaceutical sprayformulation is delivered as a spray that has a % volume <10 microns ofat most about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.5%, about2%, about 3%, about 4%, or about 5%.

In some embodiments, the pharmaceutical spray formulation is deliveredas a spray that has a span of about 1.5 to about 2.5. In someembodiments, the pharmaceutical spray formulation is delivered as aspray that has a span of about 1.5 to about 1.6, about 1.5 to about 1.7,about 1.5 to about 1.8, about 1.5 to about 1.9, about 1.5 to about 2,about 1.5 to about 2.1, about 1.5 to about 2.2, about 1.5 to about 2.3,about 1.5 to about 2.4, about 1.5 to about 2.5, about 1.6 to about 1.7,about 1.6 to about 1.8, about 1.6 to about 1.9, about 1.6 to about 2,about 1.6 to about 2.1, about 1.6 to about 2.2, about 1.6 to about 2.3,about 1.6 to about 2.4, about 1.6 to about 2.5, about 1.7 to about 1.8,about 1.7 to about 1.9, about 1.7 to about 2, about 1.7 to about 2.1,about 1.7 to about 2.2, about 1.7 to about 2.3, about 1.7 to about 2.4,about 1.7 to about 2.5, about 1.8 to about 1.9, about 1.8 to about 2,about 1.8 to about 2.1, about 1.8 to about 2.2, about 1.8 to about 2.3,about 1.8 to about 2.4, about 1.8 to about 2.5, about 1.9 to about 2,about 1.9 to about 2.1, about 1.9 to about 2.2, about 1.9 to about 2.3,about 1.9 to about 2.4, about 1.9 to about 2.5, about 2 to about 2.1,about 2 to about 2.2, about 2 to about 2.3, about 2 to about 2.4, about2 to about 2.5, about 2.1 to about 2.2, about 2.1 to about 2.3, about2.1 to about 2.4, about 2.1 to about 2.5, about 2.2 to about 2.3, about2.2 to about 2.4, about 2.2 to about 2.5, about 2.3 to about 2.4, about2.3 to about 2.5, or about 2.4 to about 2.5. In some embodiments, thepharmaceutical spray formulation is delivered as a spray that has a spanof about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about2.1, about 2.2, about 2.3, about 2.4, or about 2.5. In some embodiments,the pharmaceutical spray formulation is delivered as a spray that has aspan of at least about 1.5, about 1.6, about 1.7, about 1.8, about 1.9,about 2, about 2.1, about 2.2, about 2.3, or about 2.4. In someembodiments, the pharmaceutical spray formulation is delivered as aspray that has a span of at most about 1.6, about 1.7, about 1.8, about1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5.

In an aspect provided herein, the pharmaceutical spray formulation ispresent in and/or delivered from a device. In some embodiments, thepharmaceutical spray formulation is present in and/or delivered from apre-primed device. In some embodiments, the pharmaceutical sprayformulation is present in and/or delivered from a device suitable fordelivering the formulation into the nostril of a subject. In someembodiments, the device is a single-dose device. In some embodiments,the device is a bi-dose device. In some embodiments, the device has asingle reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 150 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device delivers twosprays of the pharmaceutical solution from a single reservoir. In someembodiments, the single-dose device delivers two sprays of thepharmaceutical solution from a single reservoir. In some embodiments,the bi-dose device delivers two sprays of the pharmaceutical solutionfrom a single reservoir. In some embodiments, the bi-dose device has afirst reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 75 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about100 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 125 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 225 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 225 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 200 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 175 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 150 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 150 μL of thepharmaceutical formulation. In some embodiments, the bi-dose devicedelivers one spray of the pharmaceutical solution from the firstreservoir and one spray of the pharmaceutical solution from the secondreservoir. In some embodiments, the pharmaceutical spray formulation ispresent in and/or delivered from a device with an oxygen absorber orscavenger. In some embodiments, the oxygen absorber or scavenger isiron, ferrous carbonate, ascorbate, or sodium bicarbonate. In someembodiments, the pharmaceutical spray formulation is present in and/ordelivered from a device wherein the device has an increased reservoir.In some embodiments, the device comprises at least one oxygen absorberor scavenger. In some embodiments, the oxygen absorber or scavenger isiron, ferrous carbonate, ascorbate, or sodium bicarbonate, or acombination thereof.

In an aspect provided herein, the pharmaceutical spray formulation isadapted for dosing by inhalation.

In an aspect provided herein, the pharmaceutical spray formulation isadapted for intranasal dosing.

In an aspect provided herein, is a spray, comprising droplets. In anaspect provided herein, is a spray delivered from a device, comprisingdroplets. In an aspect provided herein, is a spray, comprising droplets,wherein the droplets comprise epinephrine, or a pharmaceuticallyacceptable salt thereof, an isotonicity agent, and benzalkonium chlorideor chlorobutanol.

In some embodiments, the droplets comprise in aggregate from about 0.5mg to about 100 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the droplets comprise in aggregate about0.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the droplets comprise in aggregate about 1 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 2 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 3 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 4 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 5 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 6 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 7 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 8 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 9 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 10 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 15 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 20 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 25 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 30 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 35 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 40 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 45 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 50 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 55 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 60 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 65 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 70 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 75 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 80 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 85 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 90 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 95 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the droplets comprise in aggregate about 100 mg ofepinephrine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the epinephrine is at least about 10% bioavailable.In some embodiments, the epinephrine is at least about 20% bioavailable.In some embodiments, the epinephrine is at least about 30% bioavailable.In some embodiments, the epinephrine is at least about 40% bioavailable.In some embodiments, the epinephrine is at least about 50% bioavailable.In some embodiments, the epinephrine is at least about 60% bioavailable.In some embodiments, the epinephrine is at least about 70% bioavailable.In some embodiments, the epinephrine is at least about 80% bioavailable.

In some embodiments, the epinephrine, or a pharmaceutically acceptablesalt thereof, is dissolved in water, ethanol, or propylene glycol, or acombination thereof. In some embodiments, the epinephrine, or apharmaceutically acceptable salt thereof, is dissolved in water. In someembodiments, the epinephrine, or a pharmaceutically acceptable saltthereof, is dissolved in ethanol. In some embodiments, the epinephrine,or a pharmaceutically acceptable salt thereof, is dissolved in propyleneglycol. In some embodiments, the epinephrine, or a pharmaceuticallyacceptable salt thereof, is dissolved in a combination of water andethanol. In some embodiments, the epinephrine, or a pharmaceuticallyacceptable salt thereof, is dissolved in a combination of water andpropylene glycol. In some embodiments, the epinephrine, or apharmaceutically acceptable salt thereof, is dissolved in a combinationof ethanol and propylene glycol.

In some embodiments, the droplets comprise in aggregate from about0.005% to about 10% (w/v) of benzalkonium chloride or chlorobutanol.

In some embodiments, the droplets comprise in aggregate from about0.005% to about 10% (w/v) of benzalkonium chloride. In some embodiments,the pharmaceutical spray formulation comprises benzalkonium chloride ata concentration of from about 0.005% (w/v) to about 1% (w/v). In someembodiments, the pharmaceutical spray formulation comprises benzalkoniumchloride at a concentration of from about 0.01% (w/v) to about 1% (w/v).In some embodiments, the pharmaceutical spray formulation comprisesbenzalkonium chloride at a concentration of from about 0.05% (w/v) toabout 1% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises benzalkonium chloride at a concentration of fromabout 0.1% (w/v) to about 1% (w/v). In some embodiments, the dropletscomprise in aggregate from about 0.01% to about 10% (w/v) ofbenzalkonium chloride. In some embodiments, the droplets comprise inaggregate from about 0.05% to about 10% (w/v) of benzalkonium chloride.In some embodiments, the droplets comprise in aggregate from about 0.5%to about 10% (w/v) of benzalkonium chloride. In some embodiments, thedroplets comprise in aggregate from about 1% to about 10% (w/v) ofbenzalkonium chloride. In some embodiments, the droplets comprise inaggregate from about 0.005% to about 5% (w/v) of benzalkonium chloride.In some embodiments, the droplets comprise in aggregate from about 0.01%to about 2% (w/v) of benzalkonium chloride.

In some embodiments, the droplets comprise in aggregate from about0.005% to about 10% (w/v) of chlorobutanol. In some embodiments, thepharmaceutical spray formulation comprises chlorobutanol at aconcentration of from about 0.005% (w/v) to about 1% (w/v). In someembodiments, the pharmaceutical spray formulation compriseschlorobutanol at a concentration of from about 0.01% (w/v) to about 1%(w/v). In some embodiments, the pharmaceutical spray formulationcomprises chlorobutanol at a concentration of from about 0.05% (w/v) toabout 1% (w/v). In some embodiments, the pharmaceutical sprayformulation comprises chlorobutanol at a concentration of from about0.1% (w/v) to about 1% (w/v). In some embodiments, the droplets comprisein aggregate from about 0.01% to about 10% (w/v) of chlorobutanol. Insome embodiments, the droplets comprise in aggregate from about 0.05% toabout 10% (w/v) of chlorobutanol. In some embodiments, the dropletscomprise in aggregate from about 0.5% to about 10% (w/v) ofchlorobutanol. In some embodiments, the droplets comprise in aggregatefrom about 1% to about 10% (w/v) of chlorobutanol. In some embodiments,the droplets comprise in aggregate from about 0.005% to about 5% (w/v)of chlorobutanol. In some embodiments, the droplets comprise inaggregate from about 0.01% to about 2% (w/v) of chlorobutanol. In someembodiments, the droplets comprise in aggregate about 2.1% (w/v) ofchlorobutanol.

In some embodiments, the isotonicity agent is present at a concentrationof from about 0.1% to about 5% (w/v). In some embodiments, theisotonicity agent is sodium chloride.

In an aspect provided herein, the spray is delivered from a device. Insome embodiments, the device is pre-primed.

In an aspect provided herein, the spray takes the shape of a roundplume. In some embodiments, the spray takes the shape of a round plumewith an ovality ratio less than about 2.0. In some embodiments, thespray takes the shape of a round plume with an ovality ratio less thanabout 1.9. In some embodiments, the spray takes the shape of a roundplume with an ovality ratio less than about 1.8. In some embodiments,the spray takes the shape of a round plume with an ovality ratio lessthan about 1.7. In some embodiments, the spray takes the shape of around plume with an ovality ratio less than about 1.6. In someembodiments, the spray takes the shape of a round plume with an ovalityratio less than about 1.5. In some embodiments, the spray takes theshape of a round plume with an ovality ratio less than about 1.4. Insome embodiments, the spray takes the shape of a round plume with anovality ratio less than about 1.3. In some embodiments, the spray takesthe shape of a round plume with an ovality ratio less than about 1.2. Insome embodiments, the spray takes the shape of a round plume with anovality ratio less than about 1.1. In some embodiments, the spray takesthe shape of a round plume with an ovality ratio less than about 1.0. Insome embodiments, the spray takes the shape of a round plume with anovality ratio of at least about 1.0, at least about 1.1, at least about1.2, at least about 1.3, at least about 1.4, at least about 1.5, and/orno more than about 2.0, no more than about 1.9, no more than about 1.8,no more than about 1.7, no more than about 1.6, no more than about 1.5,no more than about 1.4, no more than about 1.4, no more than about 1.3,no more than about 1.2, or no more than about 1.1.

In an aspect provided herein, the ovality ratio of the spray is measuredat a distance of from about 1 cm to about 10 cm from the device fromwhich the spray is delivered. In an aspect provided herein, the ovalityratio of the spray is measured at a distance of from about 1 cm to about5 cm from the device from which the spray is delivered. In an aspectprovided herein, the ovality ratio of the spray is measured at adistance of from about 3 cm to about 6 cm from the device from which thespray is delivered. In an aspect provided herein, the ovality ratio ofthe spray is measured at a distance of about 3 cm from the device fromwhich the spray is delivered. In an aspect provided herein, the ovalityratio of the spray is measured at a distance of about 5 cm from thedevice from which the spray is delivered. In an embodiment, the spray ismeasured from a nozzle, such as a spray nozzle, on the device from whichthe spray is delivered.

In an aspect provided herein, the droplets of the spray have a mediandroplet size of from about 10 μm to about 120 μm. In some embodiments,no more than about 10% of the droplets have a diameter less than about10 μm. In some embodiments, no more than approximately 5% of thedroplets have a diameter less than about 10 μm. In some embodiments, nomore than approximately 2% of the droplets have a diameter less thanabout 10 μm. In some embodiments, approximately 50% of the droplets havea diameter of from about 10 μm to about 120 μm. In some embodiments,approximately 50% of the droplets have a diameter of from about 10 μm toabout 60 μm. In some embodiments, approximately 90% of the droplets havea diameter less than about 120 μm.

In an aspect provided herein, the spray further comprises a stabilizingagent and an acid. In some embodiments, the stabilizing agent isdisodium edetate. In some embodiments, the acid is hydrochloric acid orcitric acid, or a combination thereof. In some embodiments, the acid ishydrochloric acid. In some embodiments, the acid is citric acid. In someembodiments, the acid is a combination of hydrochloric acid and citricacid.

In an aspect provided herein, the spray further comprises sodiumbisulfite or sodium metabisulfite.

In an aspect provided herein, the spray further comprises sodiumbisulfite or sodium metabisulfite. In some embodiments, the sprayfurther comprises sodium bisulfite at a concentration of from about0.0001% (w/w) to about 0.1% (w/w) or sodium metabisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w). In someembodiments, the spray comprises sodium bisulfite at a concentration offrom about 0.0001% (w/w) to about 0.05% (w/w) or sodium metabisulfite ata concentration of from about 0.0001% (w/w) to about 0.05% (w/w). Insome embodiments, the spray comprises sodium bisulfite at aconcentration of from about 0.001% (w/w) to about 0.05% (w/w) or sodiummetabisulfite at a concentration of from about 0.001% (w/w) to about0.05% (w/w). In some embodiments, the spray comprises sodium bisulfiteat a concentration of from about 0.01% (w/w) to about 0.05% (w/w) orsodium metabisulfite at a concentration of from about 0.01% (w/w) toabout 0.05% (w/w). In some embodiments, the spray further comprisessodium bisulfite at a concentration of from about 0.001% (w/w) to about0.1% (w/w) or sodium metabisulfite at a concentration of from about0.001% (w/w) to about 0.1% (w/w). In some embodiments, the spray furthercomprises sodium bisulfite at a concentration of from about 0.01% (w/w)to about 0.1% (w/w) or sodium metabisulfite at a concentration of fromabout 0.01% (w/w) to about 0.1% (w/w).

In some embodiments, the spray comprises sodium bisulfite. In someembodiments, the spray further comprises sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w). In someembodiments, the spray comprises sodium bisulfite at a concentration offrom about 0.001% to about 0.05%. In some embodiments, the spraycomprises sodium bisulfite at a concentration of from about 0.01% toabout 0.05%. In some embodiments, the spray comprises sodium bisulfiteat a concentration of about 0.01%. In some embodiments, the spraycomprises sodium bisulfite at a concentration of about 0.02%. In someembodiments, the spray comprises sodium bisulfite at a concentration ofabout 0.03%. In some embodiments, the spray comprises sodium bisulfiteat a concentration of about 0.04%. In some embodiments, the spraycomprises sodium bisulfite at a concentration of about 0.05%.

In some embodiments, the spray comprises sodium metabisulfite. In someembodiments, the spray further comprises sodium metabisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w). In someembodiments, the spray comprises sodium metabisulfite at a concentrationof from about 0.001% to about 0.1%. In some embodiments, the spraycomprises sodium metabisulfite at a concentration of from about 0.01% toabout 0.1%. In some embodiments, the spray further comprises sodiummetabisulfite at a concentration of from about 0.001% (w/w) to about0.1% (w/w). In some embodiments, the spray further comprises sodiummetabisulfite at a concentration of from about 0.01% (w/w) to about 0.1%(w/w). In some embodiments, the spray comprises sodium metabisulfite ata concentration of about 0.01%. In some embodiments, the spray comprisessodium metabisulfite at a concentration of about 0.02%. In someembodiments, the spray comprises sodium metabisulfite at a concentrationof about 0.03%. In some embodiments, the spray comprises sodiummetabisulfite at a concentration of about 0.04%. In some embodiments,the spray comprises sodium metabisulfite at a concentration of about0.05%. In some embodiments, the spray comprises sodium metabisulfite ata concentration of about 0.06%. In some embodiments, the spray comprisessodium metabisulfite at a concentration of about 0.07%. In someembodiments, the spray comprises sodium metabisulfite at a concentrationof about 0.08%. In some embodiments, the spray comprises sodiummetabisulfite at a concentration of about 0.09%. In some embodiments,the spray comprises sodium metabisulfite at a concentration of about0.1%.

In an aspect provided herein, the spray further comprises disodiumedetate. In some embodiments, the spray comprises disodium edetate at aconcentration of from about 0.0001% to about 0.01%. In some embodiments,the spray comprises disodium edetate at a concentration of from about0.001% to about 0.01%.

In an aspect provided herein, the spray further comprises anantimicrobial preservative. In some embodiments, the antimicrobialpreservative is benzalkonium sodium or chlorobutanol. In someembodiments, the spray comprises benzalkonium sodium at a concentrationof from about 0.005% (w/v) to about 1% (w/v) or chlorobutanol at aconcentration of from about 0.005% to about 1%.

In some embodiments, the spray comprises benzalkonium sodium. In someembodiments, the spray comprises benzalkonium sodium at a concentrationof from about 0.005% to about 1%.

In some embodiments, the spray comprises chlorobutanol. In someembodiments, the spray comprises chlorobutanol at a concentration offrom about 0.005% to about 1%.

In an aspect provided herein, the spray further comprises sodiumchloride. In some embodiments, the spray comprises sodium chloride at aconcentration of from about 0.1% to about 5%. In some embodiments, thespray comprises sodium chloride at a concentration of from about 0.1% toabout 1%. In some embodiments, the spray comprises sodium chloride at aconcentration of from about 0.5% to about 5%. In some embodiments, thespray comprises sodium chloride at a concentration of from about 1% toabout 5%. In some embodiments, the spray comprises sodium chloride at aconcentration of from about 2% to about 5%. In some embodiments, thespray comprises sodium chloride at a concentration of from about 3% toabout 5%. In some embodiments, the spray comprises sodium chloride at aconcentration of from about 4% to about 5%.

In an aspect provided herein, the spray further comprises a vasodilator.In some embodiments, the vasodilator is nitroprusside, phentolamine, ornifedipine.

In some embodiments, the spray further comprises nitroprusside. In someembodiments, the spray further comprises from about 0.05 mg to about 5mg of nitroprusside. In some embodiments, the spray further comprisesfrom about 0.1 mg to about 5 mg of nitroprusside. In some embodiments,the spray further comprises from about 0.5 mg to about 5 mg ofnitroprusside. In some embodiments, the spray further comprises fromabout 1 mg to about 5 mg of nitroprusside. In some embodiments, thespray further comprises from about 1 mg to about 4 mg of nitroprusside.In some embodiments, the spray further comprises nitroprusside. In someembodiments, the spray further comprises from about 0.05 mg to about 3mg of nitroprusside. In some embodiments, the spray further comprisesnitroprusside. In some embodiments, the spray further comprises fromabout 0.5 mg to about 3 mg of nitroprusside. In some embodiments, thespray further comprises nitroprusside. In some embodiments, the sprayfurther comprises from about 0.5 mg to about 2 mg of nitroprusside.

In some embodiments, the spray further comprises phentolamine. In someembodiments, the spray further comprises from about 1 mg to about 50 mgof phentolamine. In some embodiments, the spray further comprisesphentolamine. In some embodiments, the spray further comprises fromabout 1 mg to about 40 mg of phentolamine. In some embodiments, thespray further comprises phentolamine. In some embodiments, the sprayfurther comprises from about 1 mg to about 30 mg of phentolamine. Insome embodiments, the spray further comprises phentolamine. In someembodiments, the spray further comprises from about 1 mg to about 20 mgof phentolamine. In some embodiments, the spray further comprisesphentolamine. In some embodiments, the spray further comprises fromabout 1 mg to about 10 mg of phentolamine. In some embodiments, thespray further comprises phentolamine. In some embodiments, the sprayfurther comprises from about 5 mg to about 50 mg of phentolamine. Insome embodiments, the spray further comprises phentolamine. In someembodiments, the spray further comprises from about 10 mg to about 50 mgof phentolamine. In some embodiments, the spray further comprisesphentolamine. In some embodiments, the spray further comprises fromabout 20 mg to about 50 mg of phentolamine. In some embodiments, thespray further comprises phentolamine. In some embodiments, the sprayfurther comprises from about 20 mg to about 40 mg of phentolamine.

In some embodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 10 mg to about 500mg of nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about10 mg to about 450 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 10 mg to about 400 mg of nifedipine. In someembodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 10 mg to about 350mg of nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about10 mg to about 300 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 10 mg to about 250 mg of nifedipine. In someembodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 10 mg to about 200mg of nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about10 mg to about 150 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 10 mg to about 100 mg of nifedipine. In someembodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 10 mg to about 75 mgof nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about10 mg to about 50 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 10 mg to about 40 mg of nifedipine. In someembodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 10 mg to about 30 mgof nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about50 mg to about 500 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 100 mg to about 500 mg of nifedipine. In someembodiments, the spray further comprises nifedipine. In someembodiments, the spray further comprises from about 100 mg to about 400mg of nifedipine. In some embodiments, the spray further comprisesnifedipine. In some embodiments, the spray further comprises from about100 mg to about 350 mg of nifedipine. In some embodiments, the sprayfurther comprises nifedipine. In some embodiments, the spray furthercomprises from about 100 mg to about 300 mg of nifedipine.

In an aspect provided herein, the spray further comprises a permeabilityenhancer.

In an aspect provided herein, the spray further comprises diethyleneglycol monoethyl ether. In some embodiments, the spray further comprisesdiethylene glycol monoethyl ether at a concentration of from about 0.05%to about 15%.

In an aspect provided herein, the spray further comprises a viscositymodifier. In some embodiments, the viscosity modifier is polyethyleneglycol, methylcellulose, or hypromellose.

In some embodiments, the spray further comprises polyethylene glycol. Insome embodiments, the spray further comprises from about 0.5% to about50% polyethylene glycol.

In some embodiments, the spray further comprises methylcellulose. Insome embodiments, the spray further comprises from about 0.001% to about5% methylcellulose.

In some embodiments, the spray further comprises hypromellose. In someembodiments, the spray further comprises from about 0.001% to about 0.5%hypromellose. In some embodiments, the spray further comprises fromabout 0.05% to about 0.5% hypromellose.

In an aspect provided herein, the spray comprises per 100 μL ofsolution:

from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceuticallyacceptable salt thereof;

from about 0.1 mg to about 2 mg sodium chloride;

from about 0.01 mg to about 1 mg benzalkonium chloride;

from about 0.1 mg to about 2 mg disodium edetate; and

hydrochloric acid or citric acid, or a combination thereof sufficient toachieve a pH of from about 3.5 to about 6.5.

In some embodiments, the pH of the spray is about 4. In someembodiments, the pH of the spray is about 4.5. In some embodiments, thepH of the spray is about 5. In some embodiments, the pH of the spray isabout 5.5. In some embodiments, the pH of the spray is about 6. In someembodiments, the pH of the spray is about 6.5.

In an aspect provided herein, the spray is delivered from a spray nozzleof a pre-primed device, and wherein no more than about 10% of thedroplets have a diameter less than 10 In some embodiments, the spray ismeasured by laser diffraction with beams measuring at both 3 cm and 6 cmfrom the spray nozzle.

In an aspect provided herein, the pharmaceutical spray formulation orspray is administered from a unit-dose device or delivery system. In anaspect provided herein, the pharmaceutical spray formulation or spray isadministered from a bi-dose device or delivery system. In an aspectprovided herein, the pharmaceutical spray formulation or spray isadministered from a multi-dose device or delivery system.

Pharmacokinetics

In some aspects disclosed herein, the pharmaceutical spray formulationprovides desirable pharmacokinetic profiles following administration toan individual. In some embodiments, the pharmacokinetic profilecomprises a C_(max), a T_(max), an area under curve (AUC), or anycombination thereof. In some embodiments, the administration comprises asingle spray. In some embodiments, the administration comprises twosprays. In some embodiments, the pharmaceutical spray formulationcomprises a spray in each nostril. In some embodiments, theadministration comprises one or more sprays from a unit-dose device ordelivery system. In some embodiments, the administration comprises oneor more sprays from a multi-dose or bi-dose device or delivery system.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a desired pharmacokinetic profile. In some embodiments,administration of the pharmaceutical spray formulation achieves adesired pharmacokinetic profile. In some embodiments, administration ofthe pharmaceutical spray formulation comprises a single spray, or two ormore sprays. For example, a bi-dose delivery includes a single spray ineach nostrils of an individual. In some embodiments, the desiredpharmacokinetic profile is achieved based on the pharmaceutical sprayformulation, the delivery of the pharmaceutical spray formulation, orboth. In some embodiments, the combination of the delivery device andthe pharmaceutical spray formulation achieves one or more sprays thathave a desired ovality ratio as described herein. The ovality ratio canaffect the pharmacokinetic profile, for example, by increasing the rateof absorption of the spray(s), thereby improving pharmacokineticparameters such as blood plasma concentration, C_(max), T_(max), and/orAUC of the active ingredient. The pharmaceutical spray formulation mayalso be formulated to improve absorption such as by including one ormore absorption enhancers. In some embodiments, the pharmaceutical sprayformulation comprises one or more preservatives, which can includeantioxidants, chelating agents, antimicrobial preservatives, and othertypes of preservatives that help maintain stability and/or longevity ofthe formulation. In some embodiments, the pharmaceutical sprayformulation comprises one or more buffering agents to maintain anappropriate pH for enhancing stability of the formulation. In someembodiments, the pharmaceutical spray formulation is formulated toprovide pharmacokinetics that is substantially equivalent to that ofadministration through intramuscular injection.

In some embodiments, the pharmaceutical formulation is formulated to bestable. In some embodiments, at least a minimum percentage of the activeingredient (e.g., epinephrine) remains in the pharmaceutical formulationin an un-degraded state after storage. In some embodiments, a stablepharmaceutical formulation has at least 85%, at least 90%, at least 91%,at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, or at least 99% or more of the activeingredient in an un-degraded state after a period of storage at a giventemperature and/or humidity. In some embodiments, the period of storageis at least 1 month, at least 2 months, at least 3 months, at least 4months, at least 5 months, at least 6 months, at least 7 months, atleast 8 months, at least 9 months, at least 10 months, at least 11months, or at least 12 months or more. In some embodiments, the humidityis at least 10%, at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, at least 70%, at least 80%, or at least 90% or more. Insome embodiments, a stable pharmaceutical formulation has no more than1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%,no more than 6%, no more than 7%, no more than 8%, no more than 9%, nomore than 10%, no more than 15%, or no more than 20% or more impuritiesafter a period of storage at a given temperature and/or humidity. Insome embodiments, the impurities comprise degradation products of theactive ingredient.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a blood plasma concentration of at least 0.1, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50ng/mL, and/or no more than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1, 5, 10, 15, 20, 25, or 30 ng/mL within no more than 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7,8, 9, 10, or 15 minutes. In some embodiments, the desiredpharmacokinetic profile is achieved following administration of a singlespray of the pharmaceutical spray formulation. In some embodiments, thedesired pharmacokinetic profile is achieved following administration oftwo sprays of the pharmaceutical spray formulation. In some embodiments,the desired pharmacokinetic profile is achieved following administrationof two or more sprays of the pharmaceutical spray formulation such asthree sprays, four sprays, five sprays, or six sprays. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a target blood plasma concentration within a minimum time periodfollowing administration.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a blood plasma concentration within a minimum time periodfollowing administration of about 0.1 ng/mL to about 1 ng/mL. In someembodiments, the minimum time period is about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10minutes. In some embodiments, the pharmaceutical spray formulation isformulated to achieve a blood plasma concentration within a minimum timeperiod following administration of at least about 0.1 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a blood plasma concentration within a minimum time periodfollowing administration of at most about 1 ng/mL. In some embodiments,the pharmaceutical spray formulation is formulated to achieve a bloodplasma concentration within a minimum time period followingadministration of about 0.1 ng/mL to about 0.2 ng/mL, about 0.1 ng/mL toabout 0.3 ng/mL, about 0.1 ng/mL to about 0.4 ng/mL, about 0.1 ng/mL toabout 0.5 ng/mL, about 0.1 ng/mL to about 0.6 ng/mL, about 0.1 ng/mL toabout 0.7 ng/mL, about 0.1 ng/mL to about 0.8 ng/mL, about 0.1 ng/mL toabout 0.9 ng/mL, about 0.1 ng/mL to about 1 ng/mL, about 0.2 ng/mL toabout 0.3 ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL toabout 0.5 ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL toabout 0.7 ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL toabout 0.9 ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.3 ng/mL toabout 0.4 ng/mL, about 0.3 ng/mL to about 0.5 ng/mL, about 0.3 ng/mL toabout 0.6 ng/mL, about 0.3 ng/mL to about 0.7 ng/mL, about 0.3 ng/mL toabout 0.8 ng/mL, about 0.3 ng/mL to about 0.9 ng/mL, about 0.3 ng/mL toabout 1 ng/mL, about 0.4 ng/mL to about 0.5 ng/mL, about 0.4 ng/mL toabout 0.6 ng/mL, about 0.4 ng/mL to about 0.7 ng/mL, about 0.4 ng/mL toabout 0.8 ng/mL, about 0.4 ng/mL to about 0.9 ng/mL, about 0.4 ng/mL toabout 1 ng/mL, about 0.5 ng/mL to about 0.6 ng/mL, about 0.5 ng/mL toabout 0.7 ng/mL, about 0.5 ng/mL to about 0.8 ng/mL, about 0.5 ng/mL toabout 0.9 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 0.6 ng/mL toabout 0.7 ng/mL, about 0.6 ng/mL to about 0.8 ng/mL, about 0.6 ng/mL toabout 0.9 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.7 ng/mL toabout 0.8 ng/mL, about 0.7 ng/mL to about 0.9 ng/mL, about 0.7 ng/mL toabout 1 ng/mL, about 0.8 ng/mL to about 0.9 ng/mL, about 0.8 ng/mL toabout 1 ng/mL, or about 0.9 ng/mL to about 1 ng/mL. In some embodiments,the pharmaceutical spray formulation is formulated to achieve a bloodplasma concentration within a minimum time period followingadministration of about 0.1 ng/mL, about 0.2 ng/mL, about 0.3 ng/mL,about 0.4 ng/mL, about 0.5 ng/mL, about 0.6 ng/mL, about 0.7 ng/mL,about 0.8 ng/mL, about 0.9 ng/mL, or about 1 ng/mL.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a blood plasma concentration within a minimum time periodfollowing administration of about 1 ng/mL to about 40 ng/mL. In someembodiments, the minimum time period is about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10minutes. In some embodiments, the pharmaceutical spray formulation isformulated to achieve a blood plasma concentration within a minimum timeperiod following administration of at least about 1 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a blood plasma concentration within a minimum time periodfollowing administration of at most about 40 ng/mL. In some embodiments,the pharmaceutical spray formulation is formulated to achieve a bloodplasma concentration within a minimum time period followingadministration of about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about3 ng/mL, about 1 ng/mL to about 4 ng/mL, about 1 ng/mL to about 5 ng/mL,about 1 ng/mL to about 6 ng/mL, about 1 ng/mL to about 7 ng/mL, about 1ng/mL to about 8 ng/mL, about 1 ng/mL to about 9 ng/mL, about 1 ng/mL toabout 10 ng/mL, about 1 ng/mL to about 20 ng/mL, about 1 ng/mL to about40 ng/mL, about 2 ng/mL to about 3 ng/mL, about 2 ng/mL to about 4ng/mL, about 2 ng/mL to about 5 ng/mL, about 2 ng/mL to about 6 ng/mL,about 2 ng/mL to about 7 ng/mL, about 2 ng/mL to about 8 ng/mL, about 2ng/mL to about 9 ng/mL, about 2 ng/mL to about 10 ng/mL, about 2 ng/mLto about 20 ng/mL, about 2 ng/mL to about 40 ng/mL, about 3 ng/mL toabout 4 ng/mL, about 3 ng/mL to about 5 ng/mL, about 3 ng/mL to about 6ng/mL, about 3 ng/mL to about 7 ng/mL, about 3 ng/mL to about 8 ng/mL,about 3 ng/mL to about 9 ng/mL, about 3 ng/mL to about 10 ng/mL, about 3ng/mL to about 20 ng/mL, about 3 ng/mL to about 40 ng/mL, about 4 ng/mLto about 5 ng/mL, about 4 ng/mL to about 6 ng/mL, about 4 ng/mL to about7 ng/mL, about 4 ng/mL to about 8 ng/mL, about 4 ng/mL to about 9 ng/mL,about 4 ng/mL to about 10 ng/mL, about 4 ng/mL to about 20 ng/mL, about4 ng/mL to about 40 ng/mL, about 5 ng/mL to about 6 ng/mL, about 5 ng/mLto about 7 ng/mL, about 5 ng/mL to about 8 ng/mL, about 5 ng/mL to about9 ng/mL, about 5 ng/mL to about 10 ng/mL, about 5 ng/mL to about 20ng/mL, about 5 ng/mL to about 40 ng/mL, about 6 ng/mL to about 7 ng/mL,about 6 ng/mL to about 8 ng/mL, about 6 ng/mL to about 9 ng/mL, about 6ng/mL to about 10 ng/mL, about 6 ng/mL to about 20 ng/mL, about 6 ng/mLto about 40 ng/mL, about 7 ng/mL to about 8 ng/mL, about 7 ng/mL toabout 9 ng/mL, about 7 ng/mL to about 10 ng/mL, about 7 ng/mL to about20 ng/mL, about 7 ng/mL to about 40 ng/mL, about 8 ng/mL to about 9ng/mL, about 8 ng/mL to about 10 ng/mL, about 8 ng/mL to about 20 ng/mL,about 8 ng/mL to about 40 ng/mL, about 9 ng/mL to about 10 ng/mL, about9 ng/mL to about 20 ng/mL, about 9 ng/mL to about 40 ng/mL, about 10ng/mL to about 20 ng/mL, about 10 ng/mL to about 40 ng/mL, or about 20ng/mL to about 40 ng/mL. In some embodiments, the pharmaceutical sprayformulation is formulated to achieve a blood plasma concentration withina minimum time period following administration of about 1 ng/mL, about 2ng/mL, about 3 ng/mL, about 4 ng/mL, about 5 ng/mL, about 6 ng/mL, about7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 20 ng/mL,or about 40 ng/mL.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a blood plasma concentration after a minimum time periodfollowing administration. In some embodiments, the minimum time periodis at least 1, at least 2, at least 3, at least 4, at least 5, at least6, at least 7, at least 8, at least 9, at least 10, at least 15, atleast 20, at least 30, at least 40, at least 50, at least 60, at least70, at least 80, at least 90, at least 100, at least 110, at least 120,at least 130, at least 140, or at least 150 minutes.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a blood plasma concentration after a minimum time periodfollowing administration of about 1 ng/mL to about 10 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a blood plasma concentration after a minimum time periodfollowing administration of at least about 1 ng/mL. In some embodiments,the pharmaceutical spray formulation is formulated to achieve a bloodplasma concentration after a minimum time period followingadministration of at most about 10 ng/mL. In some embodiments, thepharmaceutical spray formulation is formulated to achieve a blood plasmaconcentration after a minimum time period following administration ofabout 1 ng/mL to about 1.5 ng/mL, about 1 ng/mL to about 2 ng/mL, about1 ng/mL to about 2.5 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1ng/mL to about 3.5 ng/mL, about 1 ng/mL to about 4 ng/mL, about 1 ng/mLto about 4.5 ng/mL, about 1 ng/mL to about 5 ng/mL, about 1 ng/mL toabout 6 ng/mL, about 1 ng/mL to about 8 ng/mL, about 1 ng/mL to about 10ng/mL, about 1.5 ng/mL to about 2 ng/mL, about 1.5 ng/mL to about 2.5ng/mL, about 1.5 ng/mL to about 3 ng/mL, about 1.5 ng/mL to about 3.5ng/mL, about 1.5 ng/mL to about 4 ng/mL, about 1.5 ng/mL to about 4.5ng/mL, about 1.5 ng/mL to about 5 ng/mL, about 1.5 ng/mL to about 6ng/mL, about 1.5 ng/mL to about 8 ng/mL, about 1.5 ng/mL to about 10ng/mL, about 2 ng/mL to about 2.5 ng/mL, about 2 ng/mL to about 3 ng/mL,about 2 ng/mL to about 3.5 ng/mL, about 2 ng/mL to about 4 ng/mL, about2 ng/mL to about 4.5 ng/mL, about 2 ng/mL to about 5 ng/mL, about 2ng/mL to about 6 ng/mL, about 2 ng/mL to about 8 ng/mL, about 2 ng/mL toabout 10 ng/mL, about 2.5 ng/mL to about 3 ng/mL, about 2.5 ng/mL toabout 3.5 ng/mL, about 2.5 ng/mL to about 4 ng/mL, about 2.5 ng/mL toabout 4.5 ng/mL, about 2.5 ng/mL to about 5 ng/mL, about 2.5 ng/mL toabout 6 ng/mL, about 2.5 ng/mL to about 8 ng/mL, about 2.5 ng/mL toabout 10 ng/mL, about 3 ng/mL to about 3.5 ng/mL, about 3 ng/mL to about4 ng/mL, about 3 ng/mL to about 4.5 ng/mL, about 3 ng/mL to about 5ng/mL, about 3 ng/mL to about 6 ng/mL, about 3 ng/mL to about 8 ng/mL,about 3 ng/mL to about 10 ng/mL, about 3.5 ng/mL to about 4 ng/mL, about3.5 ng/mL to about 4.5 ng/mL, about 3.5 ng/mL to about 5 ng/mL, about3.5 ng/mL to about 6 ng/mL, about 3.5 ng/mL to about 8 ng/mL, about 3.5ng/mL to about 10 ng/mL, about 4 ng/mL to about 4.5 ng/mL, about 4 ng/mLto about 5 ng/mL, about 4 ng/mL to about 6 ng/mL, about 4 ng/mL to about8 ng/mL, about 4 ng/mL to about 10 ng/mL, about 4.5 ng/mL to about 5ng/mL, about 4.5 ng/mL to about 6 ng/mL, about 4.5 ng/mL to about 8ng/mL, about 4.5 ng/mL to about 10 ng/mL, about 5 ng/mL to about 6ng/mL, about 5 ng/mL to about 8 ng/mL, about 5 ng/mL to about 10 ng/mL,about 6 ng/mL to about 8 ng/mL, about 6 ng/mL to about 10 ng/mL, orabout 8 ng/mL to about 10 ng/mL. In some embodiments, the pharmaceuticalspray formulation is formulated to achieve a blood plasma concentrationafter a minimum time period following administration of about 1 ng/mL,about 1.5 ng/mL, about 2 ng/mL, about 2.5 ng/mL, about 3 ng/mL, about3.5 ng/mL, about 4 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 6 ng/mL,about 8 ng/mL, or about 10 ng/mL.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a C_(max) of about 0.1 ng/mL to about 1 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a C_(max) of at least about 0.1 ng/mL. In some embodiments, thepharmaceutical spray formulation is formulated to achieve a C_(max) ofat most about 1 ng/mL. In some embodiments, the pharmaceutical sprayformulation is formulated to achieve a C_(max) of about 0.1 ng/mL toabout 0.2 ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.1 ng/mL toabout 0.4 ng/mL, about 0.1 ng/mL to about 0.5 ng/mL, about 0.1 ng/mL toabout 0.6 ng/mL, about 0.1 ng/mL to about 0.7 ng/mL, about 0.1 ng/mL toabout 0.8 ng/mL, about 0.1 ng/mL to about 0.9 ng/mL, about 0.1 ng/mL toabout 1 ng/mL, about 0.2 ng/mL to about 0.3 ng/mL, about 0.2 ng/mL toabout 0.4 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.2 ng/mL toabout 0.6 ng/mL, about 0.2 ng/mL to about 0.7 ng/mL, about 0.2 ng/mL toabout 0.8 ng/mL, about 0.2 ng/mL to about 0.9 ng/mL, about 0.2 ng/mL toabout 1 ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.3 ng/mL toabout 0.5 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL toabout 0.7 ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL toabout 0.9 ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.4 ng/mL toabout 0.5 ng/mL, about 0.4 ng/mL to about 0.6 ng/mL, about 0.4 ng/mL toabout 0.7 ng/mL, about 0.4 ng/mL to about 0.8 ng/mL, about 0.4 ng/mL toabout 0.9 ng/mL, about 0.4 ng/mL to about 1 ng/mL, about 0.5 ng/mL toabout 0.6 ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, about 0.5 ng/mL toabout 0.8 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL toabout 1 ng/mL, about 0.6 ng/mL to about 0.7 ng/mL, about 0.6 ng/mL toabout 0.8 ng/mL, about 0.6 ng/mL to about 0.9 ng/mL, about 0.6 ng/mL toabout 1 ng/mL, about 0.7 ng/mL to about 0.8 ng/mL, about 0.7 ng/mL toabout 0.9 ng/mL, about 0.7 ng/mL to about 1 ng/mL, about 0.8 ng/mL toabout 0.9 ng/mL, about 0.8 ng/mL to about 1 ng/mL, or about 0.9 ng/mL toabout 1 ng/mL. In some embodiments, the pharmaceutical spray formulationis formulated to achieve a C_(max) of about 0.1 ng/mL, about 0.2 ng/mL,about 0.3 ng/mL, about 0.4 ng/mL, about 0.5 ng/mL, about 0.6 ng/mL,about 0.7 ng/mL, about 0.8 ng/mL, about 0.9 ng/mL, or about 1 ng/mL.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a C_(max) of about 1 ng/mL to about 40 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a C_(max) of at least about 1 ng/mL. In some embodiments, thepharmaceutical spray formulation is formulated to achieve a C_(max) ofat most about 40 ng/mL. In some embodiments, the pharmaceutical sprayformulation is formulated to achieve a C_(max) of about 1 ng/mL to about2 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1 ng/mL to about 4 ng/mL,about 1 ng/mL to about 5 ng/mL, about 1 ng/mL to about 6 ng/mL, about 1ng/mL to about 7 ng/mL, about 1 ng/mL to about 8 ng/mL, about 1 ng/mL toabout 9 ng/mL, about 1 ng/mL to about 10 ng/mL, about 1 ng/mL to about20 ng/mL, about 1 ng/mL to about 40 ng/mL, about 2 ng/mL to about 3ng/mL, about 2 ng/mL to about 4 ng/mL, about 2 ng/mL to about 5 ng/mL,about 2 ng/mL to about 6 ng/mL, about 2 ng/mL to about 7 ng/mL, about 2ng/mL to about 8 ng/mL, about 2 ng/mL to about 9 ng/mL, about 2 ng/mL toabout 10 ng/mL, about 2 ng/mL to about 20 ng/mL, about 2 ng/mL to about40 ng/mL, about 3 ng/mL to about 4 ng/mL, about 3 ng/mL to about 5ng/mL, about 3 ng/mL to about 6 ng/mL, about 3 ng/mL to about 7 ng/mL,about 3 ng/mL to about 8 ng/mL, about 3 ng/mL to about 9 ng/mL, about 3ng/mL to about 10 ng/mL, about 3 ng/mL to about 20 ng/mL, about 3 ng/mLto about 40 ng/mL, about 4 ng/mL to about 5 ng/mL, about 4 ng/mL toabout 6 ng/mL, about 4 ng/mL to about 7 ng/mL, about 4 ng/mL to about 8ng/mL, about 4 ng/mL to about 9 ng/mL, about 4 ng/mL to about 10 ng/mL,about 4 ng/mL to about 20 ng/mL, about 4 ng/mL to about 40 ng/mL, about5 ng/mL to about 6 ng/mL, about 5 ng/mL to about 7 ng/mL, about 5 ng/mLto about 8 ng/mL, about 5 ng/mL to about 9 ng/mL, about 5 ng/mL to about10 ng/mL, about 5 ng/mL to about 20 ng/mL, about 5 ng/mL to about 40ng/mL, about 6 ng/mL to about 7 ng/mL, about 6 ng/mL to about 8 ng/mL,about 6 ng/mL to about 9 ng/mL, about 6 ng/mL to about 10 ng/mL, about 6ng/mL to about 20 ng/mL, about 6 ng/mL to about 40 ng/mL, about 7 ng/mLto about 8 ng/mL, about 7 ng/mL to about 9 ng/mL, about 7 ng/mL to about10 ng/mL, about 7 ng/mL to about 20 ng/mL, about 7 ng/mL to about 40ng/mL, about 8 ng/mL to about 9 ng/mL, about 8 ng/mL to about 10 ng/mL,about 8 ng/mL to about 20 ng/mL, about 8 ng/mL to about 40 ng/mL, about9 ng/mL to about 10 ng/mL, about 9 ng/mL to about 20 ng/mL, about 9ng/mL to about 40 ng/mL, about 10 ng/mL to about 20 ng/mL, about 10ng/mL to about 40 ng/mL, or about 20 ng/mL to about 40 ng/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a C_(max) of about 1 ng/mL, about 2 ng/mL, about 3 ng/mL, about4 ng/mL, about 5 ng/mL, about 6 ng/mL, about 7 ng/mL, about 8 ng/mL,about 9 ng/mL, about 10 ng/mL, about 20 ng/mL, or about 40 ng/mL.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a T_(max) of no more than 10 seconds, 20 seconds, 30 seconds,40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15minutes, or 20 minutes. In some embodiments, administration of thepharmaceutical spray formulation achieves a T_(max) of at least 10seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 2minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8minutes, 9 minutes, 10 minutes, 15 minutes, or 20 minutes.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve a T_(max) of about 0.1 min to about 10 min. In someembodiments, the pharmaceutical spray formulation is formulated toachieve a T_(max) of at least about 0.1 min. In some embodiments, thepharmaceutical spray formulation is formulated to achieve a T_(max) ofat most about 10 min. In some embodiments, the pharmaceutical sprayformulation is formulated to achieve a T_(max) of about 0.1 min to about0.2 min, about 0.1 min to about 0.4 min, about 0.1 min to about 0.6 min,about 0.1 min to about 0.8 min, about 0.1 min to about 1 min, about 0.1min to about 2 min, about 0.1 min to about 4 min, about 0.1 min to about5 min, about 0.1 min to about 6 min, about 0.1 min to about 8 min, about0.1 min to about 10 min, about 0.2 min to about 0.4 min, about 0.2 minto about 0.6 min, about 0.2 min to about 0.8 min, about 0.2 min to about1 min, about 0.2 min to about 2 min, about 0.2 min to about 4 min, about0.2 min to about 5 min, about 0.2 min to about 6 min, about 0.2 min toabout 8 min, about 0.2 min to about 10 min, about 0.4 min to about 0.6min, about 0.4 min to about 0.8 min, about 0.4 min to about 1 min, about0.4 min to about 2 min, about 0.4 min to about 4 min, about 0.4 min toabout 5 min, about 0.4 min to about 6 min, about 0.4 min to about 8 min,about 0.4 min to about 10 min, about 0.6 min to about 0.8 min, about 0.6min to about 1 min, about 0.6 min to about 2 min, about 0.6 min to about4 min, about 0.6 min to about 5 min, about 0.6 min to about 6 min, about0.6 min to about 8 min, about 0.6 min to about 10 min, about 0.8 min toabout 1 min, about 0.8 min to about 2 min, about 0.8 min to about 4 min,about 0.8 min to about 5 min, about 0.8 min to about 6 min, about 0.8min to about 8 min, about 0.8 min to about 10 min, about 1 min to about2 min, about 1 min to about 4 min, about 1 min to about 5 min, about 1min to about 6 min, about 1 min to about 8 min, about 1 min to about 10min, about 2 min to about 4 min, about 2 min to about 5 min, about 2 minto about 6 min, about 2 min to about 8 min, about 2 min to about 10 min,about 4 min to about 5 min, about 4 min to about 6 min, about 4 min toabout 8 min, about 4 min to about 10 min, about 5 min to about 6 min,about 5 min to about 8 min, about 5 min to about 10 min, about 6 min toabout 8 min, about 6 min to about 10 min, or about 8 min to about 10min. In some embodiments, the pharmaceutical spray formulation isformulated to achieve a T_(max) of about 0.1 min, about 0.2 min, about0.4 min, about 0.6 min, about 0.8 min, about 1 min, about 2 min, about 4min, about 5 min, about 6 min, about 8 min, or about 10 min.

In some embodiments, the pharmaceutical spray formulation is formulatedto achieve an AUC of about 0.1 ng·h/mL to about 50 ng·h/mL. In someembodiments, the pharmaceutical spray formulation is formulated toachieve an AUC of at least about 0.1 ng·h/mL. In some embodiments, thepharmaceutical spray formulation is formulated to achieve an AUC of atmost about 50 ng·h/mL. In some embodiments, the pharmaceutical sprayformulation is formulated to achieve an AUC of about 0.1 ng·h/mL toabout 0.5 ng·h/mL, about 0.1 ng·h/mL to about 1 ng·h/mL, about 0.1ng·h/mL to about 2 ng·h/mL, about 0.1 ng·h/mL to about 4 ng·h/mL, about0.1 ng·h/mL to about 6 ng·h/mL, about 0.1 ng·h/mL to about 8 ng·h/mL,about 0.1 ng·h/mL to about 10 ng·h/mL, about 0.1 ng·h/mL to about 20ng·h/mL, about 0.1 ng·h/mL to about 30 ng·h/mL, about 0.1 ng·h/mL toabout 40 ng·h/mL, about 0.1 ng·h/mL to about 50 ng·h/mL, about 0.5ng·h/mL to about 1 ng·h/mL, about 0.5 ng·h/mL to about 2 ng·h/mL, about0.5 ng·h/mL to about 4 ng·h/mL, about 0.5 ng·h/mL to about 6 ng·h/mL,about 0.5 ng·h/mL to about 8 ng·h/mL, about 0.5 ng·h/mL to about 10ng·h/mL, about 0.5 ng·h/mL to about 20 ng·h/mL, about 0.5 ng·h/mL toabout 30 ng·h/mL, about 0.5 ng·h/mL to about 40 ng·h/mL, about 0.5ng·h/mL to about 50 ng·h/mL, about 1 ng·h/mL to about 2 ng·h/mL, about 1ng·h/mL to about 4 ng·h/mL, about 1 ng·h/mL to about 6 ng·h/mL, about 1ng·h/mL to about 8 ng·h/mL, about 1 ng·h/mL to about 10 ng·h/mL, about 1ng·h/mL to about 20 ng·h/mL, about 1 ng·h/mL to about 30 ng·h/mL, about1 ng·h/mL to about 40 ng·h/mL, about 1 ng·h/mL to about 50 ng·h/mL,about 2 ng·h/mL to about 4 ng·h/mL, about 2 ng·h/mL to about 6 ng·h/mL,about 2 ng·h/mL to about 8 ng·h/mL, about 2 ng·h/mL to about 10 ng·h/mL,about 2 ng·h/mL to about 20 ng·h/mL, about 2 ng·h/mL to about 30ng·h/mL, about 2 ng·h/mL to about 40 ng·h/mL, about 2 ng·h/mL to about50 ng·h/mL, about 4 ng·h/mL to about 6 ng·h/mL, about 4 ng·h/mL to about8 ng·h/mL, about 4 ng·h/mL to about 10 ng·h/mL, about 4 ng·h/mL to about20 ng·h/mL, about 4 ng·h/mL to about 30 ng·h/mL, about 4 ng·h/mL toabout 40 ng·h/mL, about 4 ng·h/mL to about 50 ng·h/mL, about 6 ng·h/mLto about 8 ng·h/mL, about 6 ng·h/mL to about 10 ng·h/mL, about 6 ng·h/mLto about 20 ng·h/mL, about 6 ng·h/mL to about 30 ng·h/mL, about 6ng·h/mL to about 40 ng·h/mL, about 6 ng·h/mL to about 50 ng·h/mL, about8 ng·h/mL to about 10 ng·h/mL, about 8 ng·h/mL to about 20 ng·h/mL,about 8 ng·h/mL to about 30 ng·h/mL, about 8 ng·h/mL to about 40ng·h/mL, about 8 ng·h/mL to about 50 ng·h/mL, about 10 ng·h/mL to about20 ng·h/mL, about 10 ng·h/mL to about 30 ng·h/mL, about 10 ng·h/mL toabout 40 ng·h/mL, about 10 ng·h/mL to about 50 ng·h/mL, about 20 ng·h/mLto about 30 ng·h/mL, about 20 ng·h/mL to about 40 ng·h/mL, about 20ng·h/mL to about 50 ng·h/mL, about 30 ng·h/mL to about 40 ng·h/mL, about30 ng·h/mL to about 50 ng·h/mL, or about 40 ng·h/mL to about 50 ng·h/mL.In some embodiments, the pharmaceutical spray formulation is formulatedto achieve an AUC of about 0.1 ng·h/mL, about 0.5 ng·h/mL, about 1ng·h/mL, about 2 ng·h/mL, about 4 ng·h/mL, about 6 ng·h/mL, about 8ng·h/mL, about 10 ng·h/mL, about 20 ng·h/mL, about 30 ng·h/mL, about 40ng·h/mL, or about 50 ng·h/mL.

In some embodiments, intranasal administration of the pharmaceuticalspray formulation produces an epinephrine plasma concentration that isat least 5% higher, at least 10% higher, at least 15% higher, at least20% higher, at least 25% higher, at least 30% higher, at least 35%higher, at least 40% higher, at least 45% higher, at least 50% higher,at least 60% higher, at least 70% higher, at least 80% higher, at least90% higher, at least 100% higher, at least 150% higher, at least 200%higher, at least 250% higher, at least 300% higher, at least 350%higher, at least 400% higher, at least 450% higher, at least 500%higher, at least 600% higher, at least 700% higher, at least 800%higher, at least 900% higher, or at least 1000% higher than by injectionusing a commercially available delivery device (e.g., an EpiPen) afterabout 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12, about13, about 14, or about 15 minutes following administration. In someembodiments, intranasal administration of the pharmaceutical sprayformulation results in epinephrine plasma concentrations having arelative standard deviation of no more than about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,or no more than about 100% based on plasma concentrations measuredwithin 15 minutes (inclusive) following administration. In someembodiments, intranasal administration of the pharmaceutical sprayformulation results in epinephrine plasma concentrations having arelative standard deviation that is lower than by injection using acommercially available delivery device based on plasma concentrationmeasured within 15 minutes (inclusive) following administration. In someembodiments, the plasma concentrations are measured at 1 minute and twoor more later time points within 15 minutes (inclusive).

III. Methods of Use

In another aspect is provided a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical spray formulationor a spray as described herein, including embodiments.

In an aspect provided herein is a method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising administeringto a subject in need thereof a therapeutically effective amount of apharmaceutical spray formulation or a spray as described herein,including embodiments.

In an aspect provided herein is a method of treating anaphylaxis- oranaphylactic shock-induced respiratory depression or distress,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical spray formulation or a spray asdescribed herein, including embodiments.

In another aspect is provided a method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising delivering a spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a subject in need thereof,wherein:

-   -   (i) the device is adapted for nasal delivery;    -   (ii) a volume of from about 20 μL to about 250 μL of spray is        delivered; and    -   (iii) the pharmaceutical solution comprises from about 0.5 mg to        about 100 mg of epinephrine, or a pharmaceutically acceptable        salt thereof, an isotonicity agent, and from about 0.005% to        about 1% (w/v) of benzalkonium chloride.

In some embodiments, the pharmaceutical solution comprises from about0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the pharmaceutical solution comprisesabout 0.5 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 1 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 2 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 3 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 4 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 5 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 6 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 7 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 8 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 9 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 10 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 15 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 20 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 25 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 30 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 35 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 40 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 45 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 50 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 55 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 60 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 65 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 70 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 75 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 80 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 85 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 90 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 95 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical solution comprisesabout 100 mg of epinephrine, or a pharmaceutically acceptable saltthereof.

In some embodiments, the spray delivers from about 0.5 mg to about 100mg of epinephrine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the pharmaceutical solution comprises from about 0.5mg to about 100 mg of epinephrine, or a pharmaceutically acceptable saltthereof. In some embodiments, the spray delivers about 0.5 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 1 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 2 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 3 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 4 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 5 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 6 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 7 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 8 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 9 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 10 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 15 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 20 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 25 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 30 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 35 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 40 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 45 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 50 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 55 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 60 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 65 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 70 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 75 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 80 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 85 mg of epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, the spraydelivers about 90 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the spray delivers about 95 mg ofepinephrine, or a pharmaceutically acceptable salt thereof. In someembodiments, the spray delivers about 100 mg of epinephrine, or apharmaceutically acceptable salt thereof.

In some embodiments, the plasma concentration versus time curve ofepinephrine in the subject has a t_(max) of less than from about 10minutes to about 120 minutes. In some embodiments, the plasmaconcentration versus time curve of epinephrine in the subject has at_(max) of about 5 minutes to about 50 minutes. In some embodiments, theplasma concentration versus time curve of epinephrine in the subject hasa t_(max) of about 5 minutes to about 10 minutes, about 5 minutes toabout 15 minutes, about 5 minutes to about 20 minutes, about 5 minutesto about 25 minutes, about 5 minutes to about 30 minutes, about 5minutes to about 40 minutes, about 5 minutes to about 50 minutes, about10 minutes to about 15 minutes, about 10 minutes to about 20 minutes,about 10 minutes to about 25 minutes, about 10 minutes to about 30minutes, about 10 minutes to about 40 minutes, about 10 minutes to about50 minutes, about 15 minutes to about 20 minutes, about 15 minutes toabout 25 minutes, about 15 minutes to about 30 minutes, about 15 minutesto about 40 minutes, about 15 minutes to about 50 minutes, about 20minutes to about 25 minutes, about 20 minutes to about 30 minutes, about20 minutes to about 40 minutes, about 20 minutes to about 50 minutes,about 25 minutes to about 30 minutes, about 25 minutes to about 40minutes, about 25 minutes to about 50 minutes, about 30 minutes to about40 minutes, about 30 minutes to about 50 minutes, or about 40 minutes toabout 50 minutes. In some embodiments, the plasma concentration versustime curve of epinephrine in the subject has a t_(max) of about 5minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 40 minutes, or about 50 minutes. Insome embodiments, the plasma concentration versus time curve ofepinephrine in the subject has a t_(max) of at least about 5 minutes,about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes,about 30 minutes, or about 40 minutes. In some embodiments, the plasmaconcentration versus time curve of epinephrine in the subject has at_(max) of at most about 10 minutes, about 15 minutes, about 20 minutes,about 25 minutes, about 30 minutes, about 40 minutes, or about 50minutes.

In some embodiments, a therapeutic plasma concentration of epinephrinein the subject is achieved within 15 minutes, 14 minutes, 13 minutes, 12minutes, 11 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minutefollowing administration to the subject. In some embodiments, atherapeutic plasma concentration of epinephrine in the subject isachieved in less than 20 minutes following administration to thesubject. In some embodiments, a therapeutic plasma concentration ofepinephrine in the subject is achieved in less than 15 minutes followingadministration to the subject. In some embodiments, a therapeutic plasmaconcentration of epinephrine in the subject is achieved in less than 10minutes following administration to the subject. In some embodiments, atherapeutic plasma concentration of epinephrine in the subject isachieved in less than 5 minutes following administration to the subject.In some embodiments, the therapeutic plasma concentration of epinephrinein the subject is about 500 pg/mL of epinephrine. In some embodiments,the therapeutic plasma concentration of epinephrine in the subject isabout 450 pg/mL of epinephrine. In some embodiments, the therapeuticplasma concentration of epinephrine in the subject is about 400 pg/mL ofepinephrine. In some embodiments, the therapeutic plasma concentrationof epinephrine in the subject is about 350 pg/mL of epinephrine. Inembodiments, the therapeutic plasma concentration of epinephrine in thesubject is about 300 pg/mL of epinephrine. In some embodiments, thesubject has a maximum plasma concentration (C_(max)) of from about 50pg/mL to about 500 pg/mL of epinephrine. In some embodiments, the areaunder a plasma concentration-time curve of epinephrine in the subject isfrom about 5 ng/minute/mL to about 50 ng/minute/mL.

In some embodiments, the device comprises a plunger that houses acontainer closure comprising:

(i) a vial comprising an opening;

(ii) a cannula; and

(iii) a rubber stopper; wherein the stopper is configured to occlude theopening of the vial, and wherein the cannula is configured such that thecannula can pierce the stopper when the plunger applies sufficient forceto the cannula.

In some embodiments, the pre-primed device is actuatable with one hand.In some embodiments, the device is a single-dose device. In someembodiments, the device is a bi-dose device. In some embodiments, thevolume of the reservoir is not more than about 140 μL. In someembodiments, the device has a single reservoir containing approximately125 μL of the pharmaceutical solution. In some embodiments,approximately 100 μL of the pharmaceutical solution is delivered by oneactuation of the device. In some embodiments, the device has a singlereservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 150 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device delivers twosprays of the pharmaceutical solution from a single reservoir. In someembodiments, the single-dose device delivers two sprays of thepharmaceutical solution from a single reservoir. In some embodiments,the bi-dose device delivers two sprays of the pharmaceutical solutionfrom a single reservoir. In some embodiments, the bi-dose device has afirst reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 75 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about100 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 125 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 225 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 225 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 200 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 175 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 150 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 150 μL of thepharmaceutical formulation. In some embodiments, the bi-dose devicedelivers one spray of the pharmaceutical solution from the firstreservoir and one spray of the pharmaceutical solution from the secondreservoir.

In some embodiments, delivery time of the pharmaceutical solution isless than about 25 seconds. In some embodiments, the delivery time ofthe pharmaceutical solution is less than about 20 seconds.

In some embodiments, less than about 20% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, less than about 10% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.In some embodiments, less than about 5% of the pharmaceutical solutionleaves the nasal cavity via drainage into the nasopharynx or externally.

In some embodiments, the subject is suffering from a severe allergicreaction from exposure or suspected exposure to an allergen. In someembodiments, the allergen is food, medication, or an insect bite orsting. In some embodiments, the allergen is an airborne allergen.

In some embodiments, the subject exhibits one or more symptoms chosenfrom: respiratory depression or distress, airway constriction, wheezing,tingling hands, feet, mouth, or scalp, shortness of breath, swelling orinflammation of the face, eyes, lips, tongue, or throat, hives, centralnervous system depression, cardiovascular depression, altered levelconsciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, and vomiting. In some embodiments, the subjectexhibits respiratory depression or distress, or cardiovasculardepression. In some embodiments, the subject exhibits respiratorydepression. In some embodiments, the subject exhibits respiratorydistress. In some embodiments, the subject exhibits cardiovasculardepression.

In some embodiments, the subject is free from respiratory depression ordistress for at least about 1 hour following treatment comprisingdelivery of the therapeutically effective amount of the epinephrine, ora pharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 2 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 4 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is free from respiratory depression or distress for at leastabout 6 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is in a lying, supine, or recovery position.

In some embodiments, a single spray in the nostril yields a plasmaconcentration of ≥0.2 ng/mL within 2.5 minutes in the subject. In someembodiments, a single spray in the nostril yields a plasma concentrationof ≥1 ng/mL within 5 minutes in the subject. In some embodiments, asingle spray in the nostril yields a plasma concentration of ≥3 ng/mLwithin 10 minutes in the subject. In some embodiments, a single spray inthe nostril yields a plasma concentration of ≥0.2 ng/mL within 2.5minutes in the subject. In some embodiments, a single spray in thenostril yields a plasma concentration ≥1 ng/mL within 5 minutes in thesubject. In some embodiments, a single spray in the nostril yields aplasma concentration ≥1 ng/mL within 5 minutes in the subject.

In some embodiments, the nasal spray administration described hereinprovides rapid absorption of epinephrine. In some embodiments, the nasalspray administration described herein provides absorption of epinephrinethat is substantially equivalent to that of intramuscular orsubcutaneous injection. In some embodiments, the nasal sprayadministration described herein provides pharmacokinetics that issubstantially equivalent to that of intramuscular or subcutaneousinjection. In some embodiments, described herein are methods ofadministration of a nasal spray to a subject having congested and/orinflamed nasal passageways, thereby providing rapid absorption ofepinephrine. For example, experimental data provided herein indicatecongestion enhances absorption, providing a surprising benefit. In someembodiments, a single spray in the nostril within about 1, 2, 3, 4, or 5minutes of administration yields a plasma concentration of at leastabout 0.2 ng/mL to about 3 ng/mL. In some embodiments, a single spray inthe nostril within about 1, 2, 3, 4, or 5 minutes of administrationyields a plasma concentration of at least about 0.2 ng/mL to about 0.3ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL to about 0.5ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL to about 0.7ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL to about 0.9ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 1.5ng/mL, about 0.2 ng/mL to about 2 ng/mL, about 0.2 ng/mL to about 3ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.3 ng/mL to about 0.5ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL to about 0.7ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL to about 0.9ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.3 ng/mL to about 1.5ng/mL, about 0.3 ng/mL to about 2 ng/mL, about 0.3 ng/mL to about 3ng/mL, about 0.4 ng/mL to about 0.5 ng/mL, about 0.4 ng/mL to about 0.6ng/mL, about 0.4 ng/mL to about 0.7 ng/mL, about 0.4 ng/mL to about 0.8ng/mL, about 0.4 ng/mL to about 0.9 ng/mL, about 0.4 ng/mL to about 1ng/mL, about 0.4 ng/mL to about 1.5 ng/mL, about 0.4 ng/mL to about 2ng/mL, about 0.4 ng/mL to about 3 ng/mL, about 0.5 ng/mL to about 0.6ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, about 0.5 ng/mL to about 0.8ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL to about 1ng/mL, about 0.5 ng/mL to about 1.5 ng/mL, about 0.5 ng/mL to about 2ng/mL, about 0.5 ng/mL to about 3 ng/mL, about 0.6 ng/mL to about 0.7ng/mL, about 0.6 ng/mL to about 0.8 ng/mL, about 0.6 ng/mL to about 0.9ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.6 ng/mL to about 1.5ng/mL, about 0.6 ng/mL to about 2 ng/mL, about 0.6 ng/mL to about 3ng/mL, about 0.7 ng/mL to about 0.8 ng/mL, about 0.7 ng/mL to about 0.9ng/mL, about 0.7 ng/mL to about 1 ng/mL, about 0.7 ng/mL to about 1.5ng/mL, about 0.7 ng/mL to about 2 ng/mL, about 0.7 ng/mL to about 3ng/mL, about 0.8 ng/mL to about 0.9 ng/mL, about 0.8 ng/mL to about 1ng/mL, about 0.8 ng/mL to about 1.5 ng/mL, about 0.8 ng/mL to about 2ng/mL, about 0.8 ng/mL to about 3 ng/mL, about 0.9 ng/mL to about 1ng/mL, about 0.9 ng/mL to about 1.5 ng/mL, about 0.9 ng/mL to about 2ng/mL, about 0.9 ng/mL to about 3 ng/mL, about 1 ng/mL to about 1.5ng/mL, about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about 3 ng/mL,about 1.5 ng/mL to about 2 ng/mL, about 1.5 ng/mL to about 3 ng/mL, orabout 2 ng/mL to about 3 ng/mL. In some embodiments, a single spray inthe nostril within about 1, 2, 3, 4, or 5 minutes of administrationyields a plasma concentration of at least about 0.2 ng/mL, about 0.3ng/mL, about 0.4 ng/mL, about 0.5 ng/mL, about 0.6 ng/mL, about 0.7ng/mL, about 0.8 ng/mL, about 0.9 ng/mL, about 1 ng/mL, about 1.5 ng/mL,about 2 ng/mL, or about 3 ng/mL. In some embodiments, a single spray inthe nostril within about 1, 2, 3, 4, or 5 minutes of administrationyields a plasma concentration of at least at least about 0.2 ng/mL,about 0.3 ng/mL, about 0.4 ng/mL, about 0.5 ng/mL, about 0.6 ng/mL,about 0.7 ng/mL, about 0.8 ng/mL, about 0.9 ng/mL, about 1 ng/mL, about1.5 ng/mL, or about 2 ng/mL. In some embodiments, a single spray in thenostril within about 1, 2, 3, 4, or 5 minutes of administration yields aplasma concentration of at least at most about 0.3 ng/mL, about 0.4ng/mL, about 0.5 ng/mL, about 0.6 ng/mL, about 0.7 ng/mL, about 0.8ng/mL, about 0.9 ng/mL, about 1 ng/mL, about 1.5 ng/mL, about 2 ng/mL,or about 3 ng/mL. In some embodiments, the plasma concentrationdescribed herein refers to average plasma concentration (e.g., a mean ormedian concentration determined for multiple sprays in one or bothnostrils in a subject, or sprays in multiple subjects).

In an aspect provided herein is a method of treating anaphylaxis- oranaphylactic shock-induced respiratory depression or distress,comprising delivering a spray of a pharmaceutical solution from apre-primed device into a nostril of a subject in need thereof in amanner that delivers the pharmaceutical solution in a round spray plumewith an ovality ratio less than about 2.0 when measured at a distance offrom about 1 to about 10 cm from the pre-primed device, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 μL to about 250 μL of spray is delivered;and the pharmaceutical solution comprises from about 0.5 mg to about 100mg of epinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and from about 0.005% to about 1% (w/v) ofbenzalkonium chloride.

In some embodiments, the round spray plume has an ovality ratio lessthan about 2.0. In some embodiments, the round spray plume has anovality ratio less than about 1.9. In some embodiments, the round sprayplume has an ovality ratio less than about 1.8. In some embodiments, theround spray plume has an ovality ratio less than about 1.7. In someembodiments, the round spray plume has an ovality ratio less than about1.6. In some embodiments, the round spray plume has an ovality ratioless than about 1.5. In some embodiments, the round spray plume has anovality ratio less than about 1.4. In some embodiments, the round sprayplume has an ovality ratio less than about 1.3. In some embodiments, theround spray plume has an ovality ratio less than about 1.2. In someembodiments, the round spray plume has an ovality ratio less than about1.1. In some embodiments, the round spray plume has an ovality ratioless than about 1.0.

In some embodiments, the ovality ratio of the spray is measured at adistance of from about 1 cm to about 5 cm from the device from which thespray is delivered.

In an aspect provided herein is a method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising delivering aspray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 μL to about 250 μL of spray is delivered;and

(iii) the pharmaceutical solution comprises from about 0.5 mg to about100 mg of epinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and from about 0.005% to about 1% (w/v) ofbenzalkonium chloride.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises from about 1% to about 20% w/w of epinephrine, or apharmaceutically acceptable salt thereof, from about 0.0001% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2.0% trisodium citrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises from about 5% to about 20% w/w of epinephrine, or apharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1.0%sodium chloride, from about 0.05% to about 0.5% hypromellose, from about0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5%diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises about 5% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4%sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises from about 1% to about 20% w/w of epinephrine, or apharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1%sodium chloride, from about 0.05% to about 0.5% hypromellose, from about0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about5% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises about 2% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4%sodium chloride, about 0.1% hypromellose, about 0.42% citric acidmonohydrate, and about 1% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises about 5% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4%sodium chloride, about 0.1% hypromellose, about 0.42% citric acidmonohydrate, and about 1% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises about 10% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4%sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments provided herein is a method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein the pharmaceutical spray formulationcomprises about 20% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, about 0.05% (w/w) of sodium metabisulfite, about 0.4%sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate,and about 1% diethylene glycol monoethyl ether.

In some embodiments, the subject in need thereof is an adult. In someembodiments, the subject in need thereof is a child. In someembodiments, the subject in need thereof weighs from about 10 lbs toabout 80 lbs.

IV. Device

In an aspect provided herein, the pharmaceutical solution isadministered from a unit-dose device or delivery system. In an aspectprovided herein, the pharmaceutical solution is administered from abi-dose device or delivery system. In an aspect provided herein, thepharmaceutical solution is administered from a multi-dose device ordelivery system.

In some embodiments, the device comprises: a reservoir containing atleast two doses of fluid; a dispenser member, such as a piston, that ismounted to slide in said reservoir so as to dispense the fluid; adispenser head that is provided with a dispenser orifice, said headbeing movable relative to said reservoir so as to move said actuatormember in said reservoir and thus dispense the fluid through saiddispenser orifice; said dispenser head including at least two viewingwindows, said device including an indicator that is movable togetherwith said reservoir, said indicator co-operating with a respectiveviewing window after each actuation of the device. In some embodiments,said indicator comprises at least one colored indication zone, saidindication zone appearing in said first viewing window after the firstdose of fluid has been dispensed, and in the second viewing window afterthe second dose of fluid has been dispensed. In some embodiments, saidindicator is adapted to mask colored indication zones that are providedin said dispenser head, said indicator masking a colored indication zonein said first viewing window after the first dose of fluid has beendispensed, and masking a colored indication zone in said second viewingwindow after the second dose of fluid has been dispensed. In someembodiments, said indicator is adapted to indicate, through at least oneviewing window, that an incomplete dose has been dispensed. In someembodiments, the device is held between the second and the third fingerswith the thumb on the actuator. In some embodiments, a pressure pointmechanism is incorporated in the device to secure reproducibility of theactuation force and emitted plume characteristics. In some embodiments,a cap is incorporated in the device. In some embodiments, a triggerguard on the actuator is incorporated in the device. In someembodiments, a window is incorporated in the device to view the fluid inthe reservoir. In some embodiments, a dose meter is incorporated in thedevice. In some embodiments, a mechanism is incorporated in the deviceto lock the device and prevent a second actuation of the device. In someembodiments, a timing mechanism is incorporated in the device to lockthe device and prevent a second actuation of the device after aspecified period of time.

An illustrative diagram of a device is shown in FIG. 17. The device asshown has a tip 1701 for dispensing the pharmaceutical sprayformulation, a cannula 1702 that is coupled to the tip and transportsthe formulation or solution from the reservoir 1705. Upon actuation ofthe device, a needle 1703 pierces a seal (e.g., polymeric or elastomericseal) 1704 to enter the reservoir 1705 to access the pharmaceuticalspray formulation stored as a solution within.

In some embodiments, the device is a single-dose device. In someembodiments, the device is a bi-dose device. In some embodiments, thevolume of the reservoir is not more than about 140 μL. In someembodiments, the device has a single reservoir containing approximately125 μL of the pharmaceutical solution. In some embodiments,approximately 100 μL of the pharmaceutical solution is delivered by oneactuation of the device. In some embodiments, the device has a singlereservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device has a singlereservoir containing from about 150 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the device delivers twosprays of the pharmaceutical solution from a single reservoir. In someembodiments, the single-dose device delivers two sprays of thepharmaceutical solution from a single reservoir. In some embodiments,the bi-dose device delivers two sprays of the pharmaceutical solutionfrom a single reservoir. In some embodiments, the bi-dose device has afirst reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 75 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 75 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 100 μL to about 250 μL of thepharmaceutical formulation and a second reservoir containing from about100 μL to about 250 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 125 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 225 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 225 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 200 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation. In some embodiments, the bi-dose device hasa first reservoir containing from about 50 μL to about 175 μL of thepharmaceutical formulation and a second reservoir containing from about50 μL to about 175 μL of the pharmaceutical formulation. In someembodiments, the bi-dose device has a first reservoir containing fromabout 50 μL to about 150 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 150 μL of thepharmaceutical formulation. In some embodiments, the bi-dose devicedelivers one spray of the pharmaceutical solution from the firstreservoir and one spray of the pharmaceutical solution from the secondreservoir.

In some embodiments described herein, a bi-dose device adapted for nasaldelivery of a pharmaceutical composition to a patient comprises a firstvolume of a pharmaceutical formulation in a first reservoir, and asecond volume of said pharmaceutical formulation in a second reservoir,and wherein said therapeutically effective amount of said pharmaceuticalformulation is delivered essentially by a first actuation of said drugdelivery device from said first reservoir into a nostril of a patientand a second actuation of said drug delivery device from said secondreservoir into a nostril of said patient. In some embodiments, thebi-dose device has a first reservoir containing from about 50 μL toabout 250 μL of the pharmaceutical formulation and a second reservoircontaining from about 50 μL to about 250 μL of the pharmaceuticalformulation. In some embodiments, each reservoir of the pre-primed,bi-dose device adapted for nasal delivery of a pharmaceuticalcomposition to a patient comprises between about 0.5 mg to about 100 mgof epinephrine.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises from about 1% to about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.0001% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about0.1% to about 5% sodium chloride, from about 0.001% to about 0.5%hypromellose, from about 0.01% to about 2.0% trisodium citrate, and fromabout 0.05% to about 15% diethylene glycol monoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises from about 1% to about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.0001% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about0.1% to about 5% sodium chloride, from about 0.001% to about 0.5%hypromellose, from about 0.01% to about 2.0% citric acid monohydrate,and from about 0.05% to about 15% diethylene glycol monoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises from about 5% to about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1.0% sodium chloride, from about 0.05% to about 0.5%hypromellose, from about 0.1% to about 1.0% trisodium citrate, and fromabout 0.5% to about 5% diethylene glycol monoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises from about 5% to about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1.0% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 2% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.42% citric acid monohydrate, and about 1% diethylene glycolmonoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.7% trisodium citrate, and about 1% diethylene glycol monoethylether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.42% citric acid monohydrate, and about 1% diethylene glycolmonoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 10% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.7% trisodium citrate, and about 1% diethylene glycol monoethylether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 10% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.42% citric acid monohydrate, and about 1% diethylene glycolmonoethyl ether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 20% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.7% trisodium citrate, and about 1% diethylene glycol monoethylether.

In some embodiments of the device described herein, the pharmaceuticalspray formulation comprises about 20% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.42% citric acid monohydrate, and about 1% diethylene glycolmonoethyl ether.

In some embodiments, the formulation devices and methods describedherein include a digital processing device or use of the same. Infurther embodiments, the digital processing device includes one or morehardware central processing units (CPUs) or general purpose graphicsprocessing units (GPGPUs) that carry out the device's functions. Instill further embodiments, the digital processing device furthercomprises an operating system configured to perform executableinstructions. In some embodiments, the digital processing device isoptionally connected to a computer network. In further embodiments, thedigital processing device is optionally connected to the Internet suchthat it accesses the World Wide Web. In still further embodiments, thedigital processing device is optionally connected to a cloud computinginfrastructure. In other embodiments, the digital processing device isoptionally connected to an intranet. In other embodiments, the digitalprocessing device is optionally connected to a data storage device.

In accordance with the description herein, suitable digital processingdevices include, by way of non-limiting examples, server computers,desktop computers, laptop computers, notebook computers, sub-notebookcomputers, netbook computers, netpad computers, set-top computers, mediastreaming devices, handheld computers, Internet appliances, mobilesmartphones, tablet computers, personal digital assistants, video gameconsoles, and vehicles. Those of skill in the art will recognize thatmany smartphones are suitable for use in the system described herein.Those of skill in the art will also recognize that select televisions,video players, and digital music players with optional computer networkconnectivity are suitable for use in the system described herein.Suitable tablet computers include those with booklet, slate, andconvertible configurations, known to those of skill in the art.

In some embodiments, the digital processing device includes an operatingsystem configured to perform executable instructions. The operatingsystem is, for example, software, including programs and data, whichmanages the device's hardware and provides services for execution ofapplications.

In some embodiments, the device includes a storage and/or memory device.The storage and/or memory device is one or more physical apparatusesused to store data or programs on a temporary or permanent basis. Insome embodiments, the device is volatile memory and requires power tomaintain stored information. In some embodiments, the device isnon-volatile memory and retains stored information when the digitalprocessing device is not powered. In further embodiments, thenon-volatile memory comprises flash memory. In some embodiments, thenon-volatile memory comprises dynamic random-access memory (DRAM). Insome embodiments, the non-volatile memory comprises ferroelectric randomaccess memory (FRAM). In some embodiments, the non-volatile memorycomprises phase-change random access memory (PRAM). In otherembodiments, the device is a storage device including, by way ofnon-limiting examples, CD-ROMs, DVDs, flash memory devices, magneticdisk drives, magnetic tapes drives, optical disk drives, and cloudcomputing based storage. In further embodiments, the storage and/ormemory device is a combination of devices such as those disclosedherein.

In some embodiments, the digital processing device includes a display tosend visual information to a user.

In some embodiments, the digital processing device includes an inputdevice to receive information from a user. In some embodiments, theinput device is a keyboard. In some embodiments, the input device is apointing device including, by way of non-limiting examples, a mouse,trackball, track pad, joystick, game controller, or stylus. In someembodiments, the input device is a touch screen or a multi-touch screen.In other embodiments, the input device is a microphone to capture voiceor other sound input. In other embodiments, the input device is a videocamera or other sensor to capture motion or visual input. In furtherembodiments, the input device is a Kinect, Leap Motion, or the like. Instill further embodiments, the input device is a combination of devicessuch as those disclosed herein.

Computer Program

In some embodiments, the platforms, systems, media, and methodsdisclosed herein include at least one computer program, or use of thesame. A computer program includes a sequence of instructions, executablein the digital processing device's CPU, written to perform a specifiedtask. Computer readable instructions may be implemented as programmodules, such as functions, objects, Application Programming Interfaces(APIs), data structures, and the like, that perform particular tasks orimplement particular abstract data types. In light of the disclosureprovided herein, those of skill in the art will recognize that acomputer program may be written in various versions of variouslanguages.

The functionality of the computer readable instructions may be combinedor distributed as desired in various environments. In some embodiments,a computer program comprises one sequence of instructions. In someembodiments, a computer program comprises a plurality of sequences ofinstructions. In some embodiments, a computer program is provided fromone location. In other embodiments, a computer program is provided froma plurality of locations. In various embodiments, a computer programincludes one or more software modules. In various embodiments, acomputer program includes, in part or in whole, one or more webapplications, one or more mobile applications, one or more standaloneapplications, one or more web browser plug-ins, extensions, add-ins, oradd-ons, or combinations thereof.

Mobile Application

In some embodiments, a computer program includes a mobile applicationprovided to a digital processing device or a portable device. In someembodiments, the mobile application is provided to a mobile digitalprocessing device at the time it is manufactured. In other embodiments,the mobile application is provided to a mobile digital processing devicevia the computer network described herein.

Software Modules

In some embodiments, the platforms, systems, media, and methodsdisclosed herein include software, server, and/or database modules, oruse of the same. In view of the disclosure provided herein, softwaremodules are created by techniques known to those of skill in the artusing machines, software, and languages known to the art. The softwaremodules disclosed herein are implemented in a multitude of ways. Invarious embodiments, a software module comprises a file, a section ofcode, a programming object, a programming structure, or combinationsthereof. In further various embodiments, a software module comprises aplurality of files, a plurality of sections of code, a plurality ofprogramming objects, a plurality of programming structures, orcombinations thereof. In various embodiments, the one or more softwaremodules comprise, by way of non-limiting examples, a web application, amobile application, and a standalone application. In some embodiments,software modules are in one computer program or application. In otherembodiments, software modules are in more than one computer program orapplication. In some embodiments, software modules are hosted on onemachine. In other embodiments, software modules are hosted on more thanone machine. In further embodiments, software modules are hosted oncloud computing platforms. In some embodiments, software modules arehosted on one or more machines in one location. In other embodiments,software modules are hosted on one or more machines in more than onelocation.

Databases

In some embodiments, the platforms, systems, media, and methodsdisclosed herein include one or more databases, or use of the same. Inview of the disclosure provided herein, those of skill in the art willrecognize that many databases are suitable for storage and retrieval ofinformation such as geological information and administrationinformation. In various embodiments, suitable databases include, by wayof non-limiting examples, relational databases, non-relationaldatabases, object oriented databases, object databases,entity-relationship model databases, associative databases, and XMLdatabases. Further non-limiting examples include SQL, PostgreSQL, MySQL,Oracle, DB2, and Sybase. In some embodiments, a database isinternet-based. In further embodiments, a database is web-based. Instill further embodiments, a database is cloud computing-based. In otherembodiments, a database is based on one or more local computer storagedevices.

Numbered Embodiments

The following embodiments recite nonlimiting permutations ofcombinations of features disclosed herein. Other permutations ofcombinations of features are also contemplated. 1. A pharmaceuticalspray formulation comprising from about 0.5% to about 25% w/w ofepinephrine, or a pharmaceutically acceptable salt of epinephrine, inwater, ethanol, propylene glycol, or a combination thereof; wherein thepH of the formulation is from about 4.0 to about 6.5. 2. Thepharmaceutical spray formulation of embodiment 1, comprising from about0.5% to about 10% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof. 3. The pharmaceutical spray formulation of embodiment 1 or2, wherein the pH is controlled by the addition of hydrochloric acid,citric acid, or a combination thereof. 4. The pharmaceutical sprayformulation of embodiment 3, wherein the pH is controlled by theaddition of hydrochloric acid. 5. The pharmaceutical spray formulationof embodiment 3, wherein the pH is controlled by the addition of citricacid. 6. The pharmaceutical spray formulation of embodiment 3, whereinthe pH is controlled by the addition of a combination of hydrochloricacid and citric acid. 7. The pharmaceutical spray formulation of any oneof embodiments 1-6, further comprising sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.1% (w/w). 8. The pharmaceutical spray formulation of any one ofembodiments 1-7, further comprising sodium bisulfite at a concentrationof from about 0.0001% (w/w) to about 0.05% (w/w) or sodium metabisulfiteat a concentration of from about 0.0001% (w/w) to about 0.05% (w/w). 9.The pharmaceutical spray formulation of any one of embodiments 1-8,further comprising sodium bisulfite at a concentration of from about0.0001% (w/w) to about 0.05% (w/w). 10. The pharmaceutical sprayformulation of any one of embodiments 1-8, further comprising sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.05% (w/w). 11. The pharmaceutical spray formulation of any one ofembodiments 1-10, further comprising disodium edetate at a concentrationof from about 0.0001% to about 0.01%. 12. The pharmaceutical sprayformulation of any one of embodiments 1-11, further comprising anantimicrobial preservative. 13. The pharmaceutical spray formulation ofany one of embodiments 1-12, further comprising an antimicrobialpreservative selected from benzalkonium sodium at a concentration offrom about 0.005% (w/v) to about 1% (w/v) and chlorobutanol at aconcentration of from about 0.005% (w/v) to about 1% (w/v). 14. Thepharmaceutical spray formulation of any one of embodiments 1-13, furthercomprising benzalkonium sodium at a concentration of from about 0.005%(w/v) to about 1% (w/v). 15. The pharmaceutical spray formulation of anyone of embodiments 1-13, further comprising chlorobutanol at aconcentration of from about 0.005% (w/v) to about 1% (w/v). 16. Thepharmaceutical spray formulation of any one of embodiments 1-15, furthercomprising sodium chloride at a concentration of from about 0.1% toabout 5%. 17. The pharmaceutical spray formulation of any one ofembodiments 1-16, further comprising a vasodilator. 18. Thepharmaceutical spray formulation of any one of embodiments 1-17, furthercomprising a vasodilator selected from about 0.05 mg to about 5 mg ofnitroprusside, from about 1 mg to about 50 mg of phentolamine, and fromabout 10 mg to about 500 mg of nifedipine. 19. The pharmaceutical sprayformulation of any one of embodiments 1-18, further comprising fromabout 0.05 mg to about 5 mg of nitroprusside. 20. The pharmaceuticalspray formulation of any one of embodiments 1-18, further comprisingfrom about 1 mg to about 50 mg of phentolamine. 21. The pharmaceuticalspray formulation of any one of embodiments 1-18, further comprisingfrom about 10 mg to about 500 mg of nifedipine. 22. The pharmaceuticalspray formulation of any one of embodiments 1-21, further comprising apermeability enhancer. 23. The pharmaceutical spray formulation of anyone of embodiments 1-22, further comprising diethylene glycol monoethylether at a concentration of from about 0.05% to about 15%. 24. Thepharmaceutical spray formulation of any one of embodiments 1-23, furthercomprising a viscosity modifier. 25. The pharmaceutical sprayformulation of embodiment 24, wherein the viscosity modifier is fromabout 0.5% to about 50% polyethylene glycol, from about 0.001% to about5% methylcellulose, or from about 0.001% to about 0.5% hypromellose. 26.The pharmaceutical spray formulation of any one of embodiments 1-25,further comprising from about 0.5% to about 50% polyethylene glycol. 27.The pharmaceutical spray formulation of any one of embodiments 1-25,further comprising from about 0.001% to about 5% methylcellulose. 28.The pharmaceutical spray formulation of any one of embodiments 1-25,further comprising from about 0.001% to about 0.5% hypromellose. 29. Thepharmaceutical spray formulation of any one of embodiments 1-28, furthercomprising from about 0.01% to about 2.0% trisodium citrate 30. Thepharmaceutical spray formulation of embodiment 1 comprising from about1% to about 20% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 5% sodium chloride, from about0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0%trisodium citrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether. 31. The pharmaceutical spray formulation of embodiment30 comprising from about 1% to about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1.0%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1.0% trisodium citrate, and from about 0.1% to about 2.0%diethylene glycol monoethyl ether. 32. The pharmaceutical sprayformulation of embodiment 30 comprising from about 5% to about 20% w/wof epinephrine, or a pharmaceutically acceptable salt thereof, fromabout 0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, fromabout 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5%hypromellose, from about 0.1% to about 1.0% trisodium citrate, and fromabout 0.5% to about 5% diethylene glycol monoethyl ether. 33. Thepharmaceutical spray formulation of embodiment 30 comprising about 2.4%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethyleneglycol monoethyl ether. 34. The pharmaceutical spray formulation ofembodiment 30 comprising about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.7% trisodium citrate, and about 1% diethylene glycol monoethylether. 35. The pharmaceutical spray formulation of embodiment 30comprising about 10% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, about 0.05% (w/w) of sodium metabisulfite,about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7%trisodium citrate, and about 1% diethylene glycol monoethyl ether. 36.The pharmaceutical spray formulation of embodiment 30 comprising about20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof,about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride,about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1%diethylene glycol monoethyl ether. 37. The pharmaceutical sprayformulation of any one of embodiments 30-36, further comprisingchlorobutanol at a concentration of from about 0.05% (w/v) to about 1%(w/v). 38. The pharmaceutical spray formulation of any one ofembodiments 1-37, wherein the droplet size of D50 is from about 10microns to about 100 microns. 39. The pharmaceutical spray formulationof any one of embodiments 1-38, wherein the formulation is present inand/or delivered from a device. 40. The pharmaceutical spray formulationof embodiment 39, wherein the device has an oxygen absorber orscavenger. 41. The pharmaceutical spray formulation of embodiment 40,wherein the oxygen absorber or scavenger is iron, ferrous carbonate,ascorbate, or sodium bicarbonate. 42. The pharmaceutical sprayformulation of any one of embodiments 39-41, wherein the device has anincreased reservoir. 43. The pharmaceutical spray formulation of any oneof embodiments 39-41, wherein the device is a single-dose device. 44.The pharmaceutical spray formulation of any one of embodiments 39-41,wherein the device is a bi-dose device. 45. The pharmaceutical sprayformulation of any one of embodiments 39-44, wherein the device has asingle reservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. 46. The pharmaceutical spray formulation ofembodiment 44, wherein the device has a first reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical formulation and asecond reservoir containing from about 50 μL to about 250 μL of thepharmaceutical formulation. 47. The pharmaceutical spray formulation ofany one of embodiments 1-46, wherein the formulation is adapted fordosing by inhalation. 48. The pharmaceutical spray formulation of anyone of embodiments 1-47, wherein the formulation is adapted forintranasal dosing. 49. The pharmaceutical spray formulation of any oneof embodiments 1-37, wherein the formulation is adapted for parenteraldosing. 50. A method of treating anaphylaxis, anaphylactic shock, asevere allergic reaction, and/or bronchial constriction, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a pharmaceutical spray formulation of any one of embodiments1-49. 51. A spray, comprising droplets, wherein the droplets comprise inaggregate from about 0.5 mg to about 100 mg of epinephrine, or apharmaceutically acceptable salt thereof, an isotonicity agent, and fromabout 0.005% (w/v) to about 10% (w/v) of benzalkonium chloride or fromabout 0.005% (w/v) to about 10% (w/v) chlorobutanol. 52. The spray ofembodiment 51, wherein the spray is delivered from a device. 53. Thespray of embodiment 52, wherein the device is a single-dose device. 54.The spray of embodiment 52, wherein the device is a bi-dose device. 55.The spray of any one of embodiments 52-54, wherein the device has asingle reservoir containing from about 125 μL to about 250 μL of thepharmaceutical formulation. 56. The spray of embodiment 54, wherein thedevice has a first reservoir containing from about 50 μL to about 250 μLof the pharmaceutical formulation and a second reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical formulation. 57. Thespray of any one of embodiments 52-56, wherein the device is pre-primed.58. The spray of any one of embodiments 51-57, wherein the isotonicityagent is present in a concentration from about 0.1% (w/w) to about 5%(w/w). 59. The spray of any one of embodiments 51-58, wherein theisotonicity agent is sodium chloride. 60. The spray of any one ofembodiments 51-59, wherein the spray takes the shape of a round plumewith an ovality ratio less than about 2.0. 61. The spray of any one ofembodiments 51-59, wherein the spray takes the shape of a round plumewith an ovality ratio less than about 1.5. 62. The spray of any one ofembodiments 51-59, wherein the spray takes the shape of a round plumewith an ovality ratio less than about 1.3. 63. The spray of any one ofembodiments 51-59, wherein the spray takes the shape of a round plumewith an ovality ratio less than about 1.2. 64. The spray of any one ofembodiments 51-59, wherein the spray takes the shape of a round plumewith an ovality ratio less than about 1.1. 65. The spray of any one ofembodiments 60-64, wherein the ovality ratio of the spray is measured ata distance of from about 1 cm to about 10 cm from the device. 66. Thespray of any one of embodiments 60-64, wherein the ovality ratio of thespray is measured at a distance of from about 1 cm to about 5 cm fromthe device. 67. The spray of any one of embodiments 60-64, wherein theovality ratio of the spray is measured at a distance of about 3 cm fromthe device. 68. The spray of any one of embodiments 51-67, wherein theepinephrine is at least 10% bioavailable. 69. The spray of any one ofembodiments 51-68, wherein the epinephrine is at least 40% bioavailable.70. The spray of any one of embodiments 51-69, wherein the epinephrineis at least 50% bioavailable. 71. The spray of any one of embodiments51-70, wherein the epinephrine is at least 60% bioavailable. 72. Thespray of any one of embodiments 51-71, wherein the median droplet sizeis from about 10 μm to about 120 μm. 73. The spray of any one ofembodiments 50-71, wherein no more than about 10% of the droplets have adiameter less than about 10 μm. 74. The spray of any one of embodiments51-72, wherein no more than approximately 5% of the droplets have adiameter less than about 10 μm. 75. The spray of any one of embodiments51-72, wherein no more than approximately 2% of the droplets have adiameter less than about 10 μm. 76. The spray of any one of embodiments51-72, wherein approximately 50% of the droplets have a diameter of fromabout 10 μm to about 120 μm. 77. The spray of any one of embodiments51-72, wherein approximately 50% of the droplets have a diameter of fromabout 10 μm to about 60 μm. 78. The spray of any one of embodiments51-72, wherein approximately 90% of the droplets have a diameter lessthan about 120 μm. 79. The spray of any one of embodiments 51-78,further comprising a stabilizing agent and an acid. 80. The spray ofembodiment 79, wherein the stabilizing agent is disodium edetate. 81.The spray of embodiment 79 or 80, wherein the acid is hydrochloric acidor citric acid, or a combination thereof. 82. The spray of any one ofembodiments 51-81, wherein the epinephrine, or a pharmaceuticallyacceptable salt thereof, is dissolved in water, ethanol, or propyleneglycol, or a combination thereof. 83. The spray of any one ofembodiments 51-82, further comprising sodium bisulfate at aconcentration of from about 0.0001% (w/w) to about 0.05% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.05% (w/w). 84. The spray of any one of embodiments 51-83, furthercomprising chlorobutanol at a concentration of from about 0.005% (w/v)to about 1% (w/v). 85. The spray of any one of embodiments 51-84,further comprising a vasodilator. 86. The spray of embodiment 85,wherein the vasodilator is nitroprusside, phentolamine, or nifedipine.87. The spray of any one of embodiments 51-86, further comprising apermeability enhancer. 88. The spray of embodiment 87, wherein thepermeability enhancer is diethylene glycol monoethyl ether. 89. Thespray of any one of embodiments 51-88, further comprising a viscositymodifier. 90. The spray of embodiment 89, wherein the viscosity modifieris polyethylene glycol, methylcellulose, or hypromellose. 91. The sprayof any one of embodiments 51-90, wherein the device comprises at leastone oxygen absorber or scavenger. 92. The spray of embodiment 91,wherein the at least one oxygen absorber or scavenger is iron, ferrouscarbonate, ascorbate, or sodium bicarbonate, or a combination thereof93. The spray of any one of embodiments 51-92, wherein the spraycomprises per 100 μL of solution: from about 0.5 mg to about 100 mg ofepinephrine, or a pharmaceutically acceptable salt thereof; from about0.1 mg to about 2 mg sodium chloride; from about 0.01 mg to about 1 mgbenzalkonium chloride; from about 0.1 mg to about 2 mg disodium edetate;and hydrochloric acid or citric acid, or a combination thereofsufficient to achieve a pH of from about 3.5 to about 6.5. 94. The sprayof any one of embodiments 51-93, wherein the spray is delivered from aspray nozzle of a pre-primed device, and wherein no more than about 10%of the droplets have a diameter less than 10 μm. 95. The spray ofembodiment 94, wherein the spray is measured by laser diffraction withbeams measuring at both 3 cm and 6 cm from the spray nozzle. 96. Amethod of treating anaphylaxis, anaphylactic shock, a severe allergicreaction, and/or bronchial constriction, comprising delivering a sprayof a pharmaceutical solution from a pre-primed device into a nostril ofa subject in need thereof, wherein: (i) the device is adapted for nasaldelivery; (ii) a volume of from about 20 μL to about 250 μL of spray isdelivered; and (iii) the pharmaceutical solution comprises from about0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptablesalt thereof, an isotonicity agent, and from about 0.005% (w/v) to about1% (w/v) of benzalkonium chloride. 97. The method of embodiment 96,wherein the device is a single-dose device. 98. The method of any one ofembodiment 96, wherein the device is a bi-dose device. 99. The method ofany one of embodiments 96-98, wherein the device has a single reservoircontaining from about 125 μL to about 250 μL of the pharmaceuticalsolution. 100. The method of embodiment 99, wherein the device deliverstwo sprays of the pharmaceutical solution from a single reservoir. 101.The method of embodiment 98, wherein the device has a first reservoircontaining from about 50 μL to about 250 μL of the pharmaceuticalsolution and a second reservoir containing from about 50 μL to about 250μL of the pharmaceutical solution. 102. The method of embodiment 101,wherein the device delivers one spray of the pharmaceutical solutionfrom the first reservoir and one spray of the pharmaceutical solutionfrom the second reservoir. 103. The method of any one of embodiments96-102, wherein the epinephrine, or a pharmaceutically acceptable saltthereof, is dissolved in water, ethanol, propylene glycol, or acombination thereof 104. The method of any one of embodiments 96-103,wherein the isotonicity agent is present in a concentration of fromabout 0.2% (w/w) to about 1.2% (w/v). 105. The method of any one ofembodiments 96-104, wherein the pharmaceutical solution furthercomprises from about 0.1% (w/v) to about 0.5% (w/v) of a stabilizingagent. 106. The method of any one of embodiments 96-105, wherein thepharmaceutical solution further comprises an amount of an acidsufficient to achieve a pH of from about 3.5 to about 6.5. 107. Themethod of embodiment 106, wherein the acid is hydrochloric acid orcitric acid, or a combination thereof. 108. The method of any one ofembodiments 96-107, wherein: the isotonicity agent is sodium chloride;the stabilizing agent is disodium edetate; and the acid is hydrochloricacid or citric acid, or a combination thereof. 109. The method of anyone of embodiments 96-108 wherein the plasma concentration versus timecurve of epinephrine in the subject has a tmax of less than from about10 minutes to about 120 minutes. 110. The method of any one ofembodiments 96-109, wherein the subject has a maximum plasmaconcentration (Cmax) of from about 50 pg/mL to about 500 pg/mL ofepinephrine. 111. The method of any one of embodiments 96-110, whereinthe area under a plasma concentration-time curve of epinephrine in thesubject is from about 5 ng/minute/mL to about 50 ng/minute/mL. 112. Themethod of any one of embodiments 96-111, wherein the device comprises aplunger that houses a container closure comprising: (i) a vialcomprising an opening; (ii) a cannula; and (iii) a rubber stopper;wherein the stopper is configured to occlude the opening of the vial,and wherein the cannula is configured such that the cannula can piercethe stopper when the plunger applies sufficient force to the cannula.113. The method of any one of embodiments 96-112, wherein the spraydelivers from about 0.5 mg to about 100 mg of epinephrine, or apharmaceutically acceptable salt thereof 114. The method of any one ofembodiments 96-113, wherein the pre-primed device is actuatable with onehand. 115. The method of any one of embodiments 96-114, wherein thepre-primed device has a single reservoir containing approximately 125 μLof the pharmaceutical solution. 116. The method of any one ofembodiments 96-115, wherein approximately 100 μL of the pharmaceuticalsolution is delivered by one actuation of the device. 117. The method ofany one of embodiments 96-116, wherein the volume of the reservoir isnot more than about 140 μL. 118. The method of any one of embodiments96-117, wherein delivery time of the pharmaceutical solution is lessthan about 25 seconds. 119. The method of any one of embodiments 96-117,wherein delivery time of the pharmaceutical solution is less than about20 seconds. 120. The method of any one of embodiments 96-119, whereinless than about 20% of the pharmaceutical solution leaves the nasalcavity via drainage into the nasopharynx or externally. 121. The methodof any one of embodiments 96-120, wherein less than about 10% of thepharmaceutical solution leaves the nasal cavity via drainage into thenasopharynx or externally. 122. The method of any one of embodiments96-121, wherein less than about 5% of the pharmaceutical solution leavesthe nasal cavity via drainage into the nasopharynx or externally. 123.The method of any one of embodiments 96-122, wherein the subject issuffering from a severe allergic reaction from exposure or suspectedexposure to an allergen. 124. The method of embodiment 123, wherein theallergen is food, medication, or an insect bite or sting. 125. Themethod of any one of embodiments 96-124, wherein the subject exhibitsone or more symptoms chosen from: respiratory depression or distress,airway constriction, wheezing, tingling hands, feet, mouth, or scalp,shortness of breath, swelling or inflammation of the face, eyes, lips,tongue, or throat, hives, central nervous system depression,cardiovascular depression, altered level consciousness, mydriaticpupils, hypoxemia, hypotension, unresponsiveness to stimulus,unconsciousness, stopped breathing, erratic or stopped pulse, andvomiting. 126. The method of any one of embodiments 96-125, wherein thesubject exhibits respiratory depression or distress, or cardiovasculardepression. 127. The method of any one of embodiments 96-126, whereinthe subject is free from respiratory depression or distress for at leastabout 1 hour following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof 128. The method of any one ofembodiments 96-127, wherein the subject is free from respiratorydepression or distress for at least about 2 hours following treatmentcomprising delivery of the therapeutically effective amount of theepinephrine, or a pharmaceutically acceptable salt thereof 129. Themethod of any one of embodiments 96-128, wherein the subject is freefrom respiratory depression or distress for at least about 4 hoursfollowing treatment comprising delivery of the therapeutically effectiveamount of the epinephrine, or a pharmaceutically acceptable salt thereof130. The method of any one of embodiments 96-129, wherein the subject isfree from respiratory depression or distress for at least about 6 hoursfollowing treatment comprising delivery of the therapeutically effectiveamount of the epinephrine, or a pharmaceutically acceptable salt thereof131. The method of any one of embodiments 96-130, wherein the subject isin a lying, supine, or recovery position. 132. The method of any one ofembodiments 96-131, wherein a single spray in the nostril yields aplasma concentration of 0.2 ng/mL within 2.5 minutes in the subject.133. The method of any one of embodiments 96-131, wherein a single sprayin the nostril yields a plasma concentration of 1 ng/mL within 5 minutesin the subject. 134. The method of any one of embodiments 96-131,wherein a single spray in the nostril yields a plasma concentration ofng/mL within 10 minutes in the subject. 135. A method of treatinganaphylaxis- or anaphylactic shock-induced respiratory depression ordistress, comprising delivering a spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a subject in need thereof ina manner that delivers the pharmaceutical solution in a round sprayplume with an ovality ratio less than about 2.0 when measured at adistance of from about 1 to about 10 cm from the pre-primed device,wherein: (i) the device is adapted for nasal delivery; (ii) a volume offrom about 20 μL to about 250 μL of spray is delivered; and (iii) thepharmaceutical solution comprises from about 0.5 mg to about 100 mg ofepinephrine, or a pharmaceutically acceptable salt thereof, anisotonicity agent, and from about 0.005% (w/v) to about 1% (w/v) ofbenzalkonium chloride. 136. The method of embodiment 135, wherein thedevice is a single-dose device. 137. The method of any one of embodiment135, wherein the device is a bi-dose device. 138. The method of any oneof embodiments 135-137, wherein the device has a single reservoircontaining from about 125 μL to about 250 μL of the pharmaceuticalsolution. 139. The method of embodiment 138, wherein the device deliverstwo sprays of the pharmaceutical solution from a single reservoir. 140.The method of embodiment 138, wherein the device has a first reservoircontaining from about 50 μL to about 250 μL of the pharmaceuticalsolution and a second reservoir containing from about 50 μL to about 250μL of the pharmaceutical solution. 141. The method of embodiment 140,wherein the device delivers one spray of the pharmaceutical solutionfrom the first reservoir and one spray of the pharmaceutical solutionfrom the second reservoir. 142. The method of any one of embodiments135-141, wherein the ovality ratio is less than about 1.5. 143. Themethod of any one of embodiments 135-141, wherein the ovality ratio isless than about 1.3. 144. The method of any one of embodiments 135-141,wherein the ovality ratio is less than about 1.2. 145. The method of anyone of embodiments 135-141, wherein the ovality ratio is less than about1.1. 146. The method of any one of embodiments 135-145, wherein theovality ratio of the spray is measured at a distance from about 1 cm toabout 5 cm from the device. 147. A method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising delivering aspray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein: (i) the device is adapted for nasaldelivery; (ii) a volume of from about 20 μL to about 250 μL of spray isdelivered; and (iii) the pharmaceutical solution comprises from about0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptablesalt thereof, an isotonicity agent, and from about 0.005% (w/v) to about1% (w/v) of benzalkonium chloride. 148. The method of embodiment 147,wherein the device is a single-dose device. 149. The method of any oneof embodiment 147, wherein the device is a bi-dose device. 150. Themethod of any one of embodiments 147-149, wherein the device has asingle reservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution. 151. The method of embodiment 150, wherein thedevice delivers two sprays of the pharmaceutical solution from a singlereservoir. 152. The method of embodiment 149, wherein the device has afirst reservoir containing from about 50 μL to about 250 μL of thepharmaceutical solution and a second reservoir containing from about 50μL to about 250 μL of the pharmaceutical solution. 153. The method ofembodiment 152, wherein the device delivers one spray of thepharmaceutical solution from the first reservoir and one spray of thepharmaceutical solution from the second reservoir. 154. A stablepharmaceutical spray formulation, comprising: (i) from about 1% to about25% w/w of epinephrine, or a pharmaceutically acceptable salt thereof,in water, ethanol, propylene glycol, or a combination thereof; and (ii)one or more excipients, vehicles, emulsifiers, stabilizing agents,preservatives, mucosal adhesives, antibacterial agents, buffers, and/orother additives, wherein the formulation is stable at a temperature ofat least about 20° C. and at a relative humidity of at least about 30%,and wherein the formulation is stable for a period of at least about twomonths. 155. The pharmaceutical spray formulation of embodiment 154,comprising from about 1% to about 10% w/w of epinephrine, or apharmaceutically acceptable salt thereof 156. The pharmaceutical sprayformulation of embodiment 154 or 155, wherein the formulation is stableat a temperature of at least about 25° C. 157. The pharmaceutical sprayformulation of embodiment 154 or 155, wherein the formulation is stableat a temperature of at least about 30° C. 158. The pharmaceutical sprayformulation of any one of embodiments 154-157, wherein the formulationis stable at a temperature of at least about 35° C. 159. Thepharmaceutical spray formulation of any one of embodiments 154-158,wherein the formulation is stable at a temperature of at least about 40°C. 160. The pharmaceutical spray formulation of any one of embodiments154-159, wherein the formulation is stable at a temperature of at leastabout 45° C. 161. The pharmaceutical spray formulation of any one ofembodiments 154-160, wherein the formulation is stable at a relativehumidity of at least about 40%. 162. The pharmaceutical sprayformulation of any one of embodiments 154-161, wherein the formulationis stable at a relative humidity of at least about 50%. 163. Thepharmaceutical spray formulation of any one of embodiments 154-162,wherein the formulation is stable at a relative humidity of at leastabout 60%. 164. The pharmaceutical spray formulation of any one ofembodiments 154-163, wherein the formulation is stable at a relativehumidity of at least about 70%. 165. The pharmaceutical sprayformulation of any one of embodiments 154-164, wherein the formulationis stable at a relative humidity of at least about 80%. 166. Thepharmaceutical spray formulation of any one of embodiments 154-165,wherein the formulation is stable for a period of at least about sixmonths. 167. The pharmaceutical spray formulation of any one ofembodiments 154-166, wherein the formulation is stable for a period ofat least about 12 months. 168. The pharmaceutical spray formulation ofany one of embodiments 154-167, wherein the formulation is stable for aperiod of at least about 18 months. 169. The pharmaceutical sprayformulation of any one of embodiments 154-168, wherein the formulationis stable for a period of at least about 24 months. 170. Thepharmaceutical spray formulation of any one of embodiments 154-169,wherein the formulation is stable for a period of at least about 36months. 171. The pharmaceutical spray formulation of any one ofembodiments 154-170, wherein the formulation has a viscosity of fromabout 100 to about 2,500 cP. 172. The pharmaceutical spray formulationof any one of embodiments 154-171, wherein the formulation is adaptedfor dosing by inhalation. 173. The pharmaceutical spray formulation ofany one of embodiments 154-172, wherein the formulation is adapted forintranasal dosing. 174. The pharmaceutical spray formulation of any oneof embodiments 154-171, wherein the formulation is adapted forparenteral dosing. 175. The pharmaceutical spray formulation of any oneof embodiments 154-174, further comprising an isotonicity agent presentin a concentration from about 0.1% (w/w) to about 5% (w/w). 176. Thepharmaceutical spray formulation of embodiment 175, wherein theisotonicity agent is sodium chloride. 177. The pharmaceutical sprayformulation of any one of embodiments 154-176, comprising a stabilizingagent. 178. The pharmaceutical spray formulation of embodiment 177,wherein the stabilizing agent is disodium edetate. 179. Thepharmaceutical spray formulation of any one of embodiments 154-178,further comprising an acid sufficient to achieve a pH of from about 3.5to about 6.5. 180. The pharmaceutical spray formulation of embodiment179, wherein the acid is hydrochloric acid or citric acid, or acombination thereof. 181. The pharmaceutical spray formulation of anyone of embodiments 154-180, further comprising sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.1% (w/w). 182. The pharmaceutical spray formulation of any one ofembodiments 154-181, further comprising sodium bisulfite at aconcentration of from about 0.0001% (w/w) to about 0.05% (w/w) or sodiummetabisulfite at a concentration of from about 0.0001% (w/w) to about0.05% (w/w). 183. The pharmaceutical spray formulation of any one ofembodiments 154-182, further comprising chlorobutanol at a concentrationof from about 0.005% (w/v) to about 1% (w/v). 184. The pharmaceuticalspray formulation of any one of embodiments 154-183, further comprisingfurther comprising a vasodilator. 185. The pharmaceutical sprayformulation of embodiment 184, wherein the vasodilator is nitroprusside,phentolamine, or nifedipine. 186. The pharmaceutical spray formulationof any one of embodiments 154-185, further comprising a permeabilityenhancer. 187. The pharmaceutical spray formulation of embodiment 186,wherein the permeability enhancer is diethylene glycol monoethyl ether.188. The pharmaceutical spray formulation of any one of embodiments154-187, further comprising a viscosity modifier. 189. Thepharmaceutical spray formulation of embodiment 188, wherein theviscosity modifier is polyethylene glycol, methylcellulose, orhypromellose. 190. The pharmaceutical spray formulation of any one ofembodiments 154-189, further comprising trisodium citrate. 191. Thepharmaceutical spray formulation of embodiment 154 comprising from about1% to about 20% w/w of epinephrine, or a pharmaceutically acceptablesalt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 5% sodium chloride, from about0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0%trisodium citrate, and from about 0.05% to about 15% diethylene glycolmonoethyl ether. 192. The pharmaceutical spray formulation of embodiment191 comprising from about 1% to about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, from about 0.01% (w/w) toabout 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 1.0%sodium chloride, from about 0.01% to about 0.2% hypromellose, from about0.1% to about 1.0% trisodium citrate, and from about 0.1% to about 2.0%diethylene glycol monoethyl ether. 193. The pharmaceutical sprayformulation of embodiment 191 comprising from about 5% to about 20% w/wof epinephrine, or a pharmaceutically acceptable salt thereof, fromabout 0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, fromabout 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5%hypromellose, from about 0.1% to about 1.0% trisodium citrate, and fromabout 0.5% to about 5% diethylene glycol monoethyl ether. 194. Thepharmaceutical spray formulation of embodiment 191 comprising about 2.4%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethyleneglycol monoethyl ether. 195. The pharmaceutical spray formulation ofembodiment 191 comprising about 5% w/w of epinephrine, or apharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodiummetabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose,about 0.7% trisodium citrate, and about 1% diethylene glycol monoethylether. 196. The pharmaceutical spray formulation of embodiment 191comprising about 10% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, about 0.05% (w/w) of sodium metabisulfite,about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7%trisodium citrate, and about 1% diethylene glycol monoethyl ether. 197.The pharmaceutical spray formulation of embodiment 191 comprising about20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof,about 0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride,about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1%diethylene glycol monoethyl ether. 198. The pharmaceutical sprayformulation of any one of embodiments 154-197, further comprisingchlorobutanol at a concentration of from about 0.05% (w/v) to about 1%(w/v). 199. The pharmaceutical spray formulation of any one ofembodiments 154-198, wherein the formulation is delivered from a device.200. The pharmaceutical spray formulation of embodiment 199, wherein thedevice is a single-dose device. 201. The pharmaceutical sprayformulation of any one of embodiment 199, wherein the device is abi-dose device. 202. The pharmaceutical spray formulation of any one ofembodiments 199-201, wherein the device has a single reservoircontaining from about 125 μL to about 250 μL of the pharmaceuticalsolution. 203. The pharmaceutical spray formulation of embodiment 202,wherein the device delivers two sprays of the pharmaceutical solutionfrom a single reservoir. 204. The pharmaceutical spray formulation ofembodiment 201, wherein the device has a first reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical solution and a secondreservoir containing from about 50 μL to about 250 μL of thepharmaceutical solution. 205. The pharmaceutical spray formulation ofembodiment 204, wherein the device delivers one spray of thepharmaceutical solution from the first reservoir and one spray of thepharmaceutical solution from the second reservoir. 206. Thepharmaceutical spray formulation of any one of embodiments 196-205,wherein the device is pre-primed. 207. The pharmaceutical sprayformulation of any one of embodiments 199-206, wherein the device issuitable for delivering the formulation into the nostril of a subject.208. The pharmaceutical spray formulation of any one of embodiments199-207, wherein the device comprises at least one oxygen absorber orscavenger. 209. The pharmaceutical spray formulation of embodiment 208,wherein the at least one oxygen absorber or scavenger is iron, ferrouscarbonate, ascorbate, or sodium bicarbonate, or a combination thereof210. The pharmaceutical spray formulation of any one of embodiments154-209, wherein the formulation is delivered as a spray. 211. Thepharmaceutical spray formulation of embodiment 210, wherein the spraytakes the shape of a round plume with an ovality ratio less than about2.0. 212. The pharmaceutical spray formulation of embodiment 210 or 211,wherein the spray takes the shape of a round plume with an ovality ratioless than about 1.5. 213. The pharmaceutical spray formulation of anyone of embodiments 210-212, wherein the spray takes the shape of a roundplume with an ovality ratio less than about 1.3. 214. The pharmaceuticalspray formulation of any one of embodiments 210-213, wherein the spraytakes the shape of a round plume with an ovality ratio less than about1.2. 215. The pharmaceutical spray formulation of any one of embodiments210-214, wherein the spray takes the shape of a round plume with anovality ratio less than about 1.1. 216. The pharmaceutical sprayformulation of any one of embodiments 210-215, wherein the ovality ratioof the spray is measured at a distance of from about 1 cm to about 10 cmfrom a device from which the formulation is administered or delivered.217. The pharmaceutical spray formulation of any one of embodiments210-216, wherein the ovality ratio of the spray is measured at adistance of from about 1 cm to about 5 cm from a device from which theformulation is administered or delivered. 218. The pharmaceutical sprayformulation of any one of embodiments 210-217, wherein the ovality ratioof the spray is measured at a distance of about 3 cm from a device fromwhich the formulation is administered or delivered. 219. Thepharmaceutical spray formulation of any one of embodiments 154-218,wherein the epinephrine is at least 10% bioavailable. 220. Thepharmaceutical spray formulation of any one of embodiments 154-219,wherein the epinephrine is at least 40% bioavailable. 221. Thepharmaceutical spray formulation of any one of embodiments 154-220,wherein the epinephrine is at least 50% bioavailable. 222. Thepharmaceutical spray formulation of any one of embodiments 154-221,wherein the epinephrine is at least 60% bioavailable. 223. Thepharmaceutical spray formulation of any one of embodiments 154-222,wherein the formulation comprises droplets with a median droplet sizefrom about 10 μm to about 120 μm. 224. The pharmaceutical sprayformulation of embodiment 223, wherein no more than about 10% of thedroplets have a diameter less than about 10 μm. 225. The pharmaceuticalspray formulation of embodiment 223 or 224, wherein no more thanapproximately 5% of the droplets have a diameter less than about 10 μm.226. The pharmaceutical spray formulation of any one of embodiments223-225, wherein no more than approximately 2% of the droplets have adiameter less than about 10 μm. 227. The pharmaceutical sprayformulation of any one of embodiments 223-226, wherein approximately 50%of the droplets have a diameter from about 10 μm to about 120 μm. 228.The pharmaceutical spray formulation of any one of embodiments 223-227,wherein approximately 50% of the droplets have a diameter from about 10μm to about 60 μm. 229. The pharmaceutical spray formulation of any oneof embodiments 223-228, wherein approximately 90% of the droplets have adiameter less than about 120 μm. 230. A method of treating anaphylaxis,anaphylactic shock, a severe allergic reaction, and/or bronchialconstriction, comprising administering or delivering to a subject inneed thereof the pharmaceutical spray formulation of any one ofembodiments 154-229. 231. The method of embodiment 230, wherein thepharmaceutical spray formulation is administered or delivered into anostril of the subject from a pre-primed device adapted for nasaldelivery. 232. The method of embodiment 231, wherein a volume of fromabout 20 μL to about 250 μL of spray is delivered. 233. The method ofany one of embodiments 230-232, wherein the plasma concentration versustime curve of epinephrine in the subject has a tmax of less than fromabout 10 minutes to about 120 minutes. 234. The method of any one ofembodiments 230-233, wherein a therapeutic plasma concentration ofepinephrine in the subject is achieved in less than 20 minutes followingadministration to the subject. 235. The method of any one of embodiments230-234, wherein a therapeutic plasma concentration of epinephrine inthe subject is achieved in less than 15 minutes following administrationto the subject. 236. The method of any one of embodiments 230-235,wherein a therapeutic plasma concentration of epinephrine in the subjectis achieved in less than 10 minutes following administration to thesubject. 237. The method of any one of embodiments 230-236, wherein atherapeutic plasma concentration of epinephrine in the subject isachieved in less than 5 minutes following administration to the subject.238. The method of any one of embodiments 234-237, wherein thetherapeutic plasma concentration of epinephrine in the subject is about500 pg/mL of epinephrine. 239. The method of any one of embodiments234-238, wherein the therapeutic plasma concentration of epinephrine inthe subject is about 450 pg/mL of epinephrine. 240. The method of anyone of embodiments 234-239, wherein the therapeutic plasma concentrationof epinephrine in the subject is about 400 pg/mL of epinephrine. 241.The method of any one of embodiments 234-240, wherein the therapeuticplasma concentration of epinephrine in the subject is about 350 pg/mL ofepinephrine. 242. The method of any one of embodiments 234-241, whereinthe therapeutic plasma concentration of epinephrine in the subject isabout 300 pg/mL of epinephrine. 243. The method of any one ofembodiments 230-242, wherein the subject has a maximum plasmaconcentration (Cmax) of from about 50 pg/mL to about 500 pg/mL ofepinephrine. 244. The method of any one of embodiments 230-243, whereinthe area under a plasma concentration-time curve of epinephrine in thesubject is from about 5 ng/minute/mL to about 50 ng/minute/mL. 245. Themethod of any one of embodiments 231-244, wherein the pre-primed deviceis actuatable with one hand. 246. The method of any one of embodiments231-245, wherein the pre-primed device is a single-dose device. 247. Themethod of any one of embodiments 231-245, wherein the pre-primed deviceis a bi-dose device. 248. The method of any one of embodiments 231-247,wherein the pre-primed device has a single reservoir containing fromabout 125 μL to about 250 μL of the pharmaceutical formulation. 249. Themethod of embodiment 248, wherein the device delivers two sprays of thepharmaceutical solution from a single reservoir. 250. The method ofembodiment 247, wherein the device has a first reservoir containing fromabout 50 μL to about 250 μL of the pharmaceutical solution and a secondreservoir containing from about 50 μL to about 250 μL of thepharmaceutical solution. 251. The method of embodiment 250, wherein thedevice delivers one spray of the pharmaceutical solution from the firstreservoir and one spray of the pharmaceutical solution from the secondreservoir. 252. The method of any one of embodiments 230-251, whereinapproximately 100 μL of the pharmaceutical formulation is delivered byone actuation of the device. 253. The method of embodiment 248, whereinthe volume of the reservoir is not more than about 140 μL. 254. Themethod of embodiment 250, wherein the volume of each reservoir is notmore than about 140 μL. 255. The method of any one of embodiments230-254, wherein delivery time is less than about 25 seconds. 256. Themethod of any one of embodiments 230-255, wherein delivery time is lessthan about 20 seconds. 257. The method of any one of embodiments230-256, wherein less than about 20% of the formulation leaves the nasalcavity via drainage into the nasopharynx or externally. 258. The methodof any one of embodiments 230-257, wherein less than about 10% of theformulation leaves the nasal cavity via drainage into the nasopharynx orexternally. 259. The method of any one of embodiments 230-258, whereinless than about 5% of the formulation leaves the nasal cavity viadrainage into the nasopharynx or externally. 260. The method of any oneof embodiments 230-259, wherein the subject is suffering from a severeallergic reaction from exposure or suspected exposure to an allergen.261. The method of embodiment 260, wherein the allergen is food,medication, or an insect bite or sting. 262. The method of any one ofembodiments 230-261, wherein the subject exhibits one or more symptomschosen from: respiratory depression or distress, airway constriction,wheezing, tingling hands, feet, mouth, or scalp, shortness of breath,swelling or inflammation of the face, eyes, lips, tongue, or throat,hives, central nervous system depression, cardiovascular depression,altered level consciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, and vomiting. 263. The method of any one ofembodiments 230-262, wherein the subject exhibits respiratory depressionor distress, or cardiovascular depression. 264. The method of any one ofembodiments 230-263, wherein the subject is free from respiratorydepression or distress for at least about 1 hour following treatmentcomprising delivery of the therapeutically effective amount of theepinephrine, or a pharmaceutically acceptable salt thereof 265. Themethod of any one of embodiments 230-264, wherein the subject is freefrom respiratory depression or distress for at least about 2 hoursfollowing treatment comprising delivery of the therapeutically effectiveamount of the epinephrine, or a pharmaceutically acceptable salt thereof266. The method of any one of embodiments 230-265, wherein the subjectis free from respiratory depression or distress for at least about 4hours following treatment comprising delivery of the therapeuticallyeffective amount of the epinephrine, or a pharmaceutically acceptablesalt thereof 267. The method of any one of embodiments 230-266, whereinthe subject is free from respiratory depression or distress for at leastabout 6 hours following treatment comprising delivery of thetherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof 268. The method of any one ofembodiments 230-267, wherein the subject is in a lying, supine, orrecovery position. 269. The method of any one of embodiments 230-268,wherein a single spray in the nostril yields a plasma concentration of0.2 ng/mL within 2.5 minutes in the subject. 270. The method of any oneof embodiments 230-268, wherein a single spray in the nostril yields aplasma concentration of 1 ng/mL within 5 minutes in the subject. 271.The method of any one of embodiments 230-268, wherein a single spray inthe nostril yields a plasma concentration of ng/mL within 10 minutes inthe subject. 272. A method of treating anaphylaxis- or anaphylacticshock-induced respiratory depression or distress, comprisingadministering or delivering to a subject in need thereof the sprayformulation of any one of embodiments 154-229 from a pre-primed deviceinto a nostril of the subject in a manner that delivers the formulationin a round spray plume with an ovality ratio less than about 2.0 whenmeasured at a distance of from about 1 to about 10 cm from thepre-primed device, wherein: (i) the device is adapted for nasaldelivery; and (ii) a volume of from about 20 μL to about 250 μL of sprayis delivered. 273. The method of embodiment 272, wherein the ovalityratio is less than about 1.5. 274. The method of embodiment 272, whereinthe ovality ratio is less than about 1.3. 275. The method of embodiment272, wherein the ovality ratio is less than about 1.2. 276. The methodof embodiment 272, wherein the ovality ratio is less than about 1.1.277. The method of any one of embodiments 272-276, wherein the ovalityratio of the spray is measured at a distance of from about 1 cm to about5 cm from the device. 278. A method for treating at least one symptom ofanaphylaxis or anaphylactic shock, comprising administering ordelivering to a subject in need thereof the pharmaceutical sprayformulation of any one of embodiments 154-229 from a device into anostril of the subject, wherein: (i) the device is adapted for nasaldelivery; and (ii) a volume of from about 20 μL to about 250 μL of sprayis delivered. 279. The device of any one of the preceding embodiments,wherein the device comprises: at least one processor, an operatingsystem configured to perform executable instructions, a memory, and acomputer program including instructions executable by the digitalprocessing device to create an application comprising: a) a softwaremodule sending a first notification to a portable device of a user whenthe device has been triggered for formulation administration; b) asoftware module sending a second notification to a second device of adesignated third party when the device has been triggered forformulation administration; c) a software module sending a thirdnotification to the portable device of the user when the device isoutside a predetermined range from the portable device; d) a softwaremodule sending a fourth notification to the second device of thedesignated third party when the device is outside the predeterminedrange from the portable device; e) a software module collectinggeographic data of the device when the device is in administration tothe user or a second user; f) a software module saving geographic dataof the device to a remote or cloud database; and g) a software moduleallowing the user or the second user to order a new device using thedevice or the portable device of the user. 280. The method of any one ofthe preceding embodiments, wherein the method comprising: a) sending afirst notification to a portable device of a user when the device hasbeen triggered for formulation administration; b) sending a secondnotification to a second device of a designated third party when thedevice has been triggered for formulation administration; c) sending athird notification to the portable device of the user when the device isoutside a predetermined range from the portable device; d) sending afourth notification to the second device of the designated third partywhen the device is outside the predetermined range from the portabledevice; e) collecting geographic data of the device when the device isin administration to the user or a second user; f) saving geographicdata of the device to a remote or cloud database; and g) allowing theuser or the second user to order a new device using the device or theportable device of the user. 281. The device of embodiment 279, whereinthe portable device or the second device comprises one or more of: acomputer, a notebook computer, a handheld computer, a mobilesmartphones, a tablet computer, and a personal digital assistant. 282.The device of embodiment 279 further comprising a communications elementconfigured to allow two-way data communication with the portable deviceof the user and a digital processing device using a wireless datatransfer protocol. 283. The device of embodiment 279, wherein the first,second, third, or fourth notification is sent within the application.284. The device of embodiment 279, wherein the first, second, third, orfourth notification is automatic. 285. The device of embodiment 279,wherein the first, second, third, or fourth notification comprises oneor more of: text, graphic information, sound, and vibration. 286. Apharmaceutical spray formulation comprising from about 0.5% to about 25%w/w of epinephrine, or a pharmaceutically acceptable salt ofepinephrine, in water, wherein the pH of the formulation is from about4.0 to about 6.5. 287. The pharmaceutical spray formulation ofembodiment 286, comprising from about 0.5% to about 10% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof 288. Thepharmaceutical spray formulation of embodiment 286, comprising fromabout 2% to about 5% w/w of epinephrine. 289. The pharmaceutical sprayformulation of embodiment 286, comprising about 2% w/w of epinephrine.290. The pharmaceutical spray formulation of embodiment 286, comprisingabout 5% w/w of epinephrine. 291. The pharmaceutical spray formulationof any one of embodiments 286-290, further comprising one or more of anantioxidant, an antimicrobial preservative, an isotonicity agent, anabsorption enhancer, a viscosity modifier, or a buffering agent. 292.The pharmaceutical spray formulation of embodiment 291, wherein thepharmaceutical formulation comprises an antioxidant, an antimicrobialpreservative, an isotonicity agent, an absorption enhancer, a viscositymodifier, and a buffering agent. 293. The pharmaceutical sprayformulation of any one of embodiments 286-293, further comprising anantioxidant. 294. The pharmaceutical spray formulation of embodiment293, wherein the antioxidant comprises sodium bisulfite or sodiummetabisulfite. 295. The pharmaceutical spray formulation of embodiment293, comprising the antioxidant at a concentration from about 0.0001%(w/w) to about 0.1% (w/w). 296. The pharmaceutical spray formulation ofembodiment 293, comprising the antioxidant at a concentration from about0.001% (w/w) to about 0.1% (w/w). 297. The pharmaceutical sprayformulation of embodiment 293, comprising the antioxidant at aconcentration from about 0.01% (w/w) to about 0.1% (w/w). 298. Thepharmaceutical spray formulation of embodiment 293, comprising theantioxidant at a concentration of about 0.05% (w/w). 299. Thepharmaceutical spray formulation of any one of embodiments 286-298,further comprising an antimicrobial preservative. 300. Thepharmaceutical spray formulation of embodiment 299, wherein theantimicrobial preservative comprises chlorobutanol. 301. Thepharmaceutical spray formulation of embodiment 299, comprising theantimicrobial preservative at a concentration from about 0.005% (w/v) toabout 1% (w/v). 302. The pharmaceutical spray formulation of embodiment299, comprising the antimicrobial preservative at a concentration fromabout 0.01% (w/v) to about 1% (w/v). 303. The pharmaceutical sprayformulation of embodiment 299, comprising the antimicrobial preservativeat a concentration from about 0.1% (w/v) to about 1% (w/v). 304. Thepharmaceutical spray formulation of embodiment 299, comprising theantimicrobial preservative at a concentration of about 0.21% (w/v). 305.The pharmaceutical spray formulation of embodiment 286, furthercomprising an isotonicity agent. 306. The pharmaceutical sprayformulation of embodiment 305, wherein an isotonicity agent comprisessodium chloride. 307. The pharmaceutical spray formulation of embodiment305, comprising an isotonicity agent at a concentration from about 0.1%to about 5%. 308. The pharmaceutical spray formulation of embodiment305, comprising an isotonicity agent at a concentration from about 0.1%to about 1%. 309. The pharmaceutical spray formulation of embodiment305, comprising an isotonicity agent at a concentration of about 0.4%.310. The pharmaceutical spray formulation of any one of embodiments286-309, further comprising an absorption enhancer. 311. Thepharmaceutical spray formulation of embodiment 310, wherein theabsorption enhancer comprises diethylene glycol monoethyl ether. 312.The pharmaceutical spray formulation of embodiment 310, comprising theabsorption enhancer at a concentration from about 0.05% to about 15%.313. The pharmaceutical spray formulation of embodiment 310, comprisingthe absorption enhancer at a concentration from about 0.1% to about 5%.314. The pharmaceutical spray formulation of embodiment 310, comprisingthe absorption enhancer at a concentration of about 1%. 315. Thepharmaceutical spray formulation of any one of embodiments 286-314,further comprising a viscosity modifier. 316. The pharmaceutical sprayformulation of embodiment 315, wherein the viscosity modifier compriseshypromellose. 317. The pharmaceutical spray formulation of embodiment315, comprising the viscosity modifier at a concentration from about0.001% to about 0.5%. 318. The pharmaceutical spray formulation ofembodiment 315, comprising the viscosity modifier at a concentrationfrom about 0.01% to about 0.2%. 319. The pharmaceutical sprayformulation of embodiment 315, comprising the viscosity modifier at aconcentration of about 0.1%. 320. The pharmaceutical spray formulationof any one of embodiments 286-319, further comprising a buffering agent.321. The pharmaceutical spray formulation of embodiment 320, wherein thebuffering agent comprises citric acid or citric acid monohydrate. 322.The pharmaceutical spray formulation of embodiment 320, comprising thebuffering agent at a concentration from about 0.01% to about 2%. 323.The pharmaceutical spray formulation of embodiment 320, comprising thebuffering agent at a concentration from about 0.1% to about 1%. 324. Thepharmaceutical spray formulation of embodiment 320, comprising thebuffering agent at a concentration of about 0.42%. 325. Thepharmaceutical spray formulation of embodiment 286, further comprisingsodium metabisulfite, sodium chloride, hypromellose, citric acidmonohydrate, and diethylene glycol monoethyl ether. 326. Thepharmaceutical spray formulation of embodiment 325, comprising fromabout 1% to about 20% w/w of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) ofsodium metabisulfite, from about 0.1% to about 5% sodium chloride, fromabout 0.001% to about 0.5% hypromellose, from about 0.01% to about 2%citric acid monohydrate, and from about 0.05% to about 15% diethyleneglycol monoethyl ether. 327. The pharmaceutical spray formulation ofembodiment 325, comprising from about 1% to about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether. 328. Thepharmaceutical spray formulation of embodiment 325, comprising about 2%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, fromabout 0.0001% (w/w) to about 0.1% (w/w) of sodium metabisulfite, fromabout 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5%hypromellose, from about 0.01% to about 2% citric acid monohydrate, andfrom about 0.05% to about 15% diethylene glycol monoethyl ether. 329.The pharmaceutical spray formulation of embodiment 325, comprising about2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof,from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, fromabout 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether. 330. Thepharmaceutical spray formulation of embodiment 325, comprising about 2%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. 331. The pharmaceutical sprayformulation of embodiment 325, comprising about 5% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. 332. The pharmaceuticalspray formulation of embodiment 325, comprising about 5% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether. 333. Thepharmaceutical spray formulation of embodiment 325, comprising about 5%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. 334. The pharmaceutical sprayformulation of embodiment 325, comprising about 10% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. 335. The pharmaceuticalspray formulation of embodiment 325, comprising about 10% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether. 336. Thepharmaceutical spray formulation of embodiment 325, comprising about 10%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. 337. The pharmaceutical sprayformulation of embodiment 325, comprising about 20% w/w of epinephrine,or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w)to about 0.1% (w/w) of sodium metabisulfite, from about 0.1% to about 5%sodium chloride, from about 0.001% to about 0.5% hypromellose, fromabout 0.01% to about 2% citric acid monohydrate, and from about 0.05% toabout 15% diethylene glycol monoethyl ether. 338. The pharmaceuticalspray formulation of embodiment 325, comprising about 20% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, from about0.01% (w/w) to about 0.1% (w/w) of sodium metabisulfite, from about 0.1%to about 1% sodium chloride, from about 0.01% to about 0.2%hypromellose, from about 0.1% to about 1% citric acid monohydrate, andfrom about 0.1% to about 5% diethylene glycol monoethyl ether. 339. Thepharmaceutical spray formulation of embodiment 325, comprising about 20%w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about0.05% (w/w) of sodium metabisulfite, about 0.4% sodium chloride, about0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1%diethylene glycol monoethyl ether. 340. The pharmaceutical sprayformulation of any one of embodiments 286-339, further comprisingchlorobutanol at a concentration of from about 0.005% (w/v) to about 10%(w/v). 341. The pharmaceutical spray formulation of any one ofembodiments 286-339, further comprising chlorobutanol at a concentrationof from about 0.01% (w/v) to about 10% (w/v). 342. The pharmaceuticalspray formulation of any one of embodiments 286-339, further comprisingchlorobutanol at a concentration of from about 0.1% (w/v) to about 1%(w/v). 343. The pharmaceutical spray formulation of any one ofembodiments 286-339, further comprising chlorobutanol at a concentrationabout 0.21% (w/v). 344. A spray, comprising droplets, wherein thedroplets comprise the pharmaceutical spray formulation of any one ofembodiments 286-343. 345. A method of treating anaphylaxis, anaphylacticshock, a severe allergic reaction, and/or bronchial constriction,comprising delivering a spray of a pharmaceutical solution from apre-primed device into a nostril of a subject in need thereof, wherein:(i) the device is adapted for nasal delivery; (ii) a volume of fromabout 20 μL to about 250 μL of spray is delivered; and (iii) thepharmaceutical solution comprises the pharmaceutical spray formulationof any one of embodiments 286-343. 346. A method of treatinganaphylaxis- or anaphylactic shock-induced respiratory depression ordistress, comprising delivering a spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a subject in need thereof ina manner that delivers the pharmaceutical solution in a round sprayplume with an ovality ratio less than about 2.0 when measured at adistance of from about 1 to about 10 cm from the pre-primed device,wherein: (i) the device is adapted for nasal delivery; (ii) a volume offrom about 20 μL to about 250 μL of spray is delivered; and (iii) thepharmaceutical solution comprises the pharmaceutical spray formulationof any one of embodiments 286-343. 347. A method for treating at leastone symptom of anaphylaxis or anaphylactic shock, comprising deliveringa spray of a pharmaceutical solution from a device into a nostril of asubject in need thereof, wherein: (i) the device is adapted for nasaldelivery; (ii) a volume of from about 20 μL to about 250 μL of spray isdelivered; and the pharmaceutical solution comprises the pharmaceuticalspray formulation of any one of embodiments 286-343. 348. The method ofany one of embodiments 345-347, wherein a therapeutic plasmaconcentration of epinephrine in the subject is achieved in less than 20minutes following administration to the subject. 349. The method of anyone of embodiments 345-347, wherein the therapeutic plasma concentrationof epinephrine in the subject is about 0.5 ng/mL of epinephrine. 350.The method of any one of embodiments 345-347, wherein the subject has amaximum plasma concentration (Cmax) of from about 0.1 ng/mL to about 1ng/mL of epinephrine. 351. The method of any one of embodiments 345-347,wherein the area under a plasma concentration-time curve of epinephrinein the subject is from about 0.1 ng·h/mL to about 5 ng·h/mL. 352. Themethod of any one of embodiments 345-347, wherein the plasmaconcentration versus time curve of epinephrine in the subject has a tmaxof less than from about 10 minutes to about 120 minutes 353. The methodof any one of embodiments 345-352, wherein the device is a single-dosedevice. 354. The method of any one of embodiments 345-352, wherein thedevice is a bi-dose device. 355. The method of any one of embodiments345-354, wherein the device delivers two sprays of the pharmaceuticalsolution from a single reservoir. 356. The method of any one ofembodiments 345-354, wherein the device has a first reservoir containingfrom about 50 μL to about 250 μL of the pharmaceutical solution and asecond reservoir containing from about 50 μL to about 250 μL of thepharmaceutical solution. 357. The method of any one of embodiments345-356, wherein less than about 20% of the formulation leaves the nasalcavity via drainage into the nasopharynx or externally. 358. The methodof any one of embodiments 345-357, wherein a single spray in a nostrilof the subject yields a plasma concentration of at least 0.2 ng/mLwithin 2 minutes in the subject. 359. A stable pharmaceutical sprayformulation, comprising: (i) from about 1% to about 25% w/w ofepinephrine, or a pharmaceutically acceptable salt thereof, in water;and (ii) one or more excipients, vehicles, emulsifiers, stabilizingagents, preservatives, mucosal adhesives, antibacterial agents, buffers,and/or other additives, wherein the formulation is stable at atemperature of at least about 20° C. and at a relative humidity of atleast about 30%, and wherein the formulation is stable for a period ofat least about two months, wherein the stable pharmaceutical formulationis the pharmaceutical spray formulation from any one of embodiments286-343. 360. A pharmaceutical spray formulation, comprising: (i) fromabout 1% to about 25% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof, in water, ethanol, propylene glycol, or acombination thereof; and (ii) one or more of an antioxidant, anantimicrobial preservative, an isotonicity agent, an absorptionenhancer, a viscosity modifier, or a buffering agent; wherein theformulation is configured to be administered into a nostril of a subjectas a nasal spray that yields a plasma concentration of at least 0.5ng/mL within 1 minute of administration. 361. The pharmaceutical sprayformulation of embodiment 360, wherein the pH of the formulation is fromabout 4.0 to about 6.5. 362. The pharmaceutical spray formulation ofembodiment 360 or 361, wherein the antioxidant comprises sodiumbisulfate or sodium metabisulfite at a concentration from about 0.01% toabout 0.1% (w/w). 363. The pharmaceutical spray formulation of any oneof embodiments 360-362, wherein the antimicrobial preservative compriseschlorobutanol or chlorobutanol hemihydrate at a concentration from about0.1% to about 1% (w/w). 364. The pharmaceutical spray formulation of anyone of embodiments 360-363, wherein the isotonicity agent comprisessodium chloride at a concentration from about 0.1% to about 1% (w/w).365. The pharmaceutical spray formulation of any one of embodiments360-364, wherein the viscosity modifier comprises hypromellose at aconcentration from about 0.01% to about 0.2% (w/w). 366. Thepharmaceutical spray formulation of any one of embodiments 360-365,wherein the buffering agent comprises citric acid or citric acidmonohydrate at a concentration from about 0.1% to about 1% (w/w). 367.The pharmaceutical spray formulation of any one of embodiments 360-366,comprising about 2% or about 5% (w/w) of epinephrine, or apharmaceutically acceptable salt thereof 368. The pharmaceutical sprayformulation of any one of embodiments 360-367, wherein thepharmaceutical spray formulation comprises sodium metabisulfite, sodiumchloride, hypromellose, citric acid monohydrate, diethylene glycolmonoethyl ether, and chlorobutanol hemihydrate. 369. The pharmaceuticalspray formulation of any one of embodiments 360-367, comprising fromabout 1% to about 10% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof, from about 0.01% to about 0.1% (w/w) of sodiummetabisulfite, from about 0.1% to about 1% (w/w) sodium chloride, fromabout 0.01% to about 0.2% (w/w) hypromellose, from about 0.1% to about1% (w/w) citric acid monohydrate, from about 0.1% to about 5% (w/w)diethylene glycol monoethyl ether, and from about 0.1% to about 1% (w/w)chlorobutanol hemihydrate. 370. A stable pharmaceutical sprayformulation, comprising: (a) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the formulation is stable for a period of at least about onemonth at a temperature of at least about 20° C. 371. The pharmaceuticalspray formulation of embodiment 370, wherein the formulation is stablefor a period of at least one month at a temperature of at least about40° C. 372. The pharmaceutical spray formulation of embodiment 370 or371, wherein the formulation has no more than about 2% total impuritiesafter storage for a period of at least about one month at a temperatureof at least about 40° C. 373. The pharmaceutical spray formulation ofany one of embodiments 370-372, wherein the antioxidant comprises sodiumbisulfite or sodium metabisulfite at a concentration from about 0.01% toabout 0.1% (w/w). 374. The pharmaceutical spray formulation of any oneof embodiments 370-373, wherein the antimicrobial preservative compriseschlorobutanol or chlorobutanol hemihydrate at a concentration from about0.1% to about 1% (w/w). 375. The pharmaceutical spray formulation of anyone of embodiments 370-374, wherein the isotonicity agent comprisessodium chloride at a concentration from about 0.1% to about 1% (w/w).376. The pharmaceutical spray formulation of any one of embodiments370-375, wherein the buffering agent comprises citric acid or citricacid monohydrate at a concentration from about 0.1% to about 1% (w/w).377. A pharmaceutical spray formulation, comprising: (i) from about 1%to about 25% (w/w) of epinephrine, or a pharmaceutically acceptable saltthereof, in water, ethanol, propylene glycol, or a combination thereof;and (ii) one or more of an antioxidant, an antimicrobial preservative,an isotonicity agent, an absorption enhancer, a viscosity modifier, or abuffering agent; wherein the absorption enhancer is diethylene glycolmonoethyl ether. 378. The pharmaceutical spray formulation of embodiment377, wherein the formulation comprises diethylene glycol monoethyl etherat a concentration from about 0.1% to about 5% (w/w). 379. Thepharmaceutical spray formulation of embodiment 377 or 378, wherein theabsorption enhancer comprises diethylene glycol monoethyl ether at aconcentration of about 1% (w/w). 380. A method for treating at least onesymptom of anaphylaxis or anaphylactic shock, comprising delivering aspray of a pharmaceutical spray formulation from a nasal spray deviceinto a nostril of a subject in need thereof, wherein the pharmaceuticalspray formulation comprises: (a) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the formulation is configured to be administered into a nostrilof a subject as a nasal spray that yields a plasma concentration of atleast 0.5 ng/mL within 1 minute of administration. 381. The method ofembodiment 380, wherein the subject is suffering from a severe allergicreaction from exposure or suspected exposure to an allergen. 382. Themethod of embodiment 381, wherein the allergen is food, medication, oran insect bite or sting. 383. The method of any one of embodiments380-382, wherein the subject exhibits one or more symptoms chosen from:respiratory depression or distress, airway constriction, wheezing,tingling hands, feet, mouth, or scalp, shortness of breath, swelling orinflammation of the face, eyes, lips, tongue, or throat, hives, centralnervous system depression, cardiovascular depression, altered levelconsciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, and vomiting. 384. The method of any one ofembodiments 380-383, wherein the subject exhibits respiratory depressionor distress, or cardiovascular depression. 385. The method of any one ofembodiments 380-384, wherein the subject is free from respiratorydepression or distress for at least about 1 hour following delivery ofthe pharmaceutical spray formulation. 386. The method of any one ofembodiments 380-385, wherein the antioxidant comprises sodium bisulfiteor sodium metabisulfite at a concentration from about 0.01% to about0.1% (w/w). 387. The method of any one of embodiments 380-386, whereinthe antimicrobial preservative comprises chlorobutanol or chlorobutanolhemihydrate at a concentration from about 0.1% to about 1% (w/w). 388.The method of any one of embodiments 380-387, wherein the isotonicityagent comprises sodium chloride at a concentration from about 0.1% toabout 1% (w/w). 389. The method of any one of embodiments 380-388,wherein the viscosity modifier comprises hypromellose at a concentrationfrom about 0.01% to about 0.2% (w/w). 390. The method of any one ofembodiments 380-389, wherein the buffering agent comprises citric acidor citric acid monohydrate at a concentration from about 0.1% to about1% (w/w). 391. The method of any one of embodiments 380-390, comprisingabout 2% or about 5% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof. 392. The method of any one of embodiments380-391, wherein the pharmaceutical spray formulation comprises sodiummetabisulfite, sodium chloride, hypromellose, citric acid monohydrate,diethylene glycol monoethyl ether, and chlorobutanol hemihydrate. 393. Amethod of treating at least one of anaphylaxis, anaphylactic shock, asevere allergic reaction, or bronchial constriction, comprisingadministering or delivering to a subject in need thereof a stablepharmaceutical spray formulation, wherein the stable pharmaceuticalspray formulation comprises: (a) from about 1% to about 25% (w/w) ofepinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the formulation is stable for a period of at least about onemonth at a temperature of at least about 20° C. 394. The method ofembodiment 393, wherein the formulation is stable for a period of atleast one month at a temperature of at least about 40° C. 395. Themethod of embodiment 393 or 394, wherein the formulation comprises nomore than 2% total impurities after storage for a period of at leastabout one month at a temperature of at least about 40° C. 396. A methodof treating at least one of anaphylaxis, anaphylactic shock, a severeallergic reaction, or bronchial constriction, comprising administeringor delivering to a subject in need thereof the pharmaceutical sprayformulation, wherein the pharmaceutical spray formulation comprises: (c)from about 1% to about 25% (w/w) of epinephrine, or a pharmaceuticallyacceptable salt thereof, in water, ethanol, propylene glycol, or acombination thereof; and (d) one or more of an antioxidant, anantimicrobial preservative, an isotonicity agent, an absorptionenhancer, a viscosity modifier, or a buffering agent; wherein atherapeutic plasma concentration of epinephrine in the subject isachieved in less than 15 minutes following administration to thesubject. 397. The method of embodiment 396, wherein the absorptionenhancer is diethylene glycol monoethyl ether. 398. The method ofembodiment 396 or 397, wherein the formulation comprises diethyleneglycol monoethyl ether at a concentration from about 0.1% to about 5%(w/w). 399. The method of any one of embodiments 396-398, wherein theformulation comprises diethylene glycol monoethyl ether at aconcentration of about 1% (w/w). 400. A bi-dose nasal delivery deviceadapted for delivery of a pharmaceutical solution into a nostril of asubject, comprising: (a) the pharmaceutical solution configured as apharmaceutical spray formulation comprising from about 1% to about 25%(w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, inwater, ethanol, propylene glycol, or a combination thereof; (b) areservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution; and wherein the bi-dose device is configured toadminister the pharmaceutical solution into a nostril of a subject astwo nasal sprays. 401. The device of embodiment 400, wherein the deviceis a pre-primed device that is configured to be actuatable with onehand. 402. The device of embodiment 400 or 401, wherein the device isconfigured to deliver about 100 μL of the pharmaceutical solution fromthe reservoir upon each actuation of the device. 403. The device of anyone of embodiments 400-402, wherein the pH of the pharmaceuticalsolution is from about 4.0 to about 6.5. 404. The device of any one ofembodiments 400-403, wherein one or more sprays take the shape of around plume with an ovality ratio less than about 2.0. 405. The deviceof any one of embodiments 400-404, wherein the pharmaceutical solutioncomprises an antioxidant. 406. The device of embodiment 405, wherein theantioxidant comprises sodium bisulfite or sodium metabisulfite at aconcentration from about 0.01% to about 0.1% (w/w). 407. The device ofany one of embodiments 400-406, wherein the pharmaceutical solutioncomprises an antimicrobial preservative. 408. The device of embodiment407, wherein the antimicrobial preservative comprises chlorobutanol orchlorobutanol hemihydrate at a concentration from about 0.1% to about 1%(w/w). 409. The device of any one of embodiments 400-408, wherein thepharmaceutical solution comprises an isotonicity agent. 410. The deviceof embodiment 409, wherein the isotonicity agent comprises sodiumchloride at a concentration from about 0.1% to about 1% (w/w). 411. Thedevice of any one of embodiments 400-410, wherein the pharmaceuticalsolution comprises a viscosity modifier. 412. The device of embodiment411, wherein the viscosity modifier comprises hypromellose at aconcentration from about 0.01% to about 0.2% (w/w). 413. The device ofany one of embodiments 400-412, wherein the pharmaceutical solutioncomprises a buffering agent. 414. The device of embodiment 413, whereinthe buffering agent comprises citric acid or citric acid monohydrate ata concentration from about 0.1% to about 1% (w/w). 415. The device ofany one of embodiments 400-414, wherein the pharmaceutical solutioncomprises about 2% or about 5% (w/w) of epinephrine, or apharmaceutically acceptable salt thereof 416. A pre-primed deviceadapted for delivery of a pharmaceutical solution into one or bothnostrils of a subject, comprising a reservoir containing from about 125μL to about 250 μL of the pharmaceutical solution, wherein thepharmaceutical solution comprises: (a) from about 1% to about 25% (w/w)of epinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the pre-primed device is configured to administer thepharmaceutical solution as one or more sprays into one or both nostrilsof the subject. 417. The device of embodiment 416, wherein theformulation comprises diethylene glycol monoethyl ether at aconcentration from about 0.1% to about 5% (w/w). 418. A bi-dose deviceadapted for delivery of a pharmaceutical solution into one or bothnostrils of a subject, comprising a reservoir containing from about 125μL to about 250 μL of the pharmaceutical solution, wherein thepharmaceutical solution comprises: (a) from about 1% to about 25% (w/w)of epinephrine, or a pharmaceutically acceptable salt thereof, in water,ethanol, propylene glycol, or a combination thereof; and (b) one or moreof an antioxidant, an antimicrobial preservative, an isotonicity agent,an absorption enhancer, a viscosity modifier, or a buffering agent;wherein the pharmaceutical solution is stable for a period of at leastabout one month at a temperature of at least about 20° C. 419. Thedevice of embodiment 418, wherein the pharmaceutical solution is stablefor a period of at least about three months at a temperature of at leastabout 20° C. 420. A method of administering a pharmaceutical solution,comprising delivering a spray of the pharmaceutical solution from adevice into a nostril of a subject in need thereof in a manner thatdelivers the pharmaceutical solution in a round spray plume with anovality ratio less than about 1.4 when measured at a distance of fromabout 1 to about 10 cm from the device, wherein: (i) the device isadapted for nasal delivery; (ii) a volume of from about 20 μL to about250 μL of spray is delivered; and (iii) the pharmaceutical solutioncomprises from about 0.5 mg to about 100 mg of epinephrine, or apharmaceutically acceptable salt thereof 421. The method of embodiment420, wherein the spray plume has a particle size distribution with aspan of no more than about 2.2 when measured at a distance of from about1 to about 10 cm from the device. 422. The method of embodiment 420 or421, wherein the spray plume has a Dmax of less than about 28 mm whenmeasured at a distance of from about 1 to about 10 cm from the device.423. The method of any one of embodiments 420-422, wherein the device isa bi-dose device configured to deliver two sprays of the pharmaceuticalsolution. 424. The method of any one of embodiments 420-423, wherein thedevice has a single reservoir containing from about 125 μL to about 250μL of the pharmaceutical solution. 425. The method of any one ofembodiments 420-424, wherein the device comprises a plunger that housesa container closure comprising: (i) a vial comprising an opening; (ii) acannula; and (iii) a rubber stopper; wherein the stopper is configuredto occlude the opening of the vial, and wherein the cannula isconfigured such that the cannula can pierce the stopper when the plungerapplies sufficient force to the cannula. 426. The method of any one ofembodiments 420-426, wherein the device is a pre-primed device that isconfigured to be actuatable with one hand. 427. The method of any one ofembodiments 420-427, wherein a delivery time of the pharmaceuticalsolution is less than about 25 seconds. 428. The method of any one ofembodiments 420-427, wherein the subject is suffering from a severeallergic reaction from exposure or suspected exposure to an allergen.429. The method of embodiment 428, wherein the allergen is food,medication, or an insect bite or sting. 430. The method of any one ofembodiments 420-429, wherein the subject exhibits one or more symptomschosen from: respiratory depression or distress, airway constriction,wheezing, tingling hands, feet, mouth, or scalp, shortness of breath,swelling or inflammation of the face, eyes, lips, tongue, or throat,hives, central nervous system depression, cardiovascular depression,altered level consciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, or vomiting. 431. The method of any one ofembodiments 420-430, wherein the subject exhibits respiratory depressionor distress, or cardiovascular depression. 432. The method of embodiment431, wherein the subject is free from respiratory depression or distressfor at least about 1 hour following treatment comprising delivery of atherapeutically effective amount of the epinephrine, or apharmaceutically acceptable salt thereof 433. A method of administeringa pharmaceutical solution, comprising delivering a spray of thepharmaceutical solution from a device into a nostril of a subject inneed thereof in a manner that delivers the pharmaceutical solution in aspray plume with a particle size distribution having a span of no morethan about 2.2 when measured at a distance of from about 1 to about 10cm from the device, wherein: (i) the device is adapted for nasaldelivery; (ii) a volume of from about 20 μL to about 250 μL of spray isdelivered; and (iii) the pharmaceutical solution comprises from about0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptablesalt thereof. 434. The method of embodiment 433, wherein the particlesize distribution has a span of no more than about 2.0 when measured ata distance of from about 1 to about 10 cm from the device. 435. Themethod of embodiment 433 or 434, wherein the device has a singlereservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution. 436. The method of any one of embodiments433-435, wherein the device is a bi-dose device configured to delivertwo sprays of the pharmaceutical solution from a single reservoir. 437.A method for administering a pharmaceutical solution, comprisingdelivering a spray of the pharmaceutical solution from a device into anostril of a subject in need thereof in a manner that delivers thepharmaceutical solution in a spray plume with a Dmax of less than about28 mm when measured at a distance of from about 1 to about 10 cm fromthe device, wherein: (i) the device is adapted for nasal delivery; (ii)a volume of from about 20 μL to about 250 μL of spray is delivered; and(iii) the pharmaceutical solution comprises from about 0.5 mg to about100 mg of epinephrine, or a pharmaceutically acceptable salt thereof438. The method of embodiment 437, wherein the device is a bi-dosedevice configured to deliver two sprays of the pharmaceutical solution.439. The method of embodiment 437 or 438, wherein the Dmax is less thanabout 26 mm when measured at a distance of from about 1 to about 10 cmfrom the device.

EXAMPLES Example 1: Epinephrine Spray Formulation and Related Studies

TABLE 1 Epinephrine Spray Formulation Raw Material Compendia CAS #Amount g (−) -Epinephrine USP 51-43-4  0.05 g Sodium Ph. Eur., BP,7681-57-4 0.001 g metabisulfite or NF HCl* Ph. Eur., BP, 7647-01-0 q.s.to pH 4.7 +/− 0.2 or USP/NF NaCl Ph. Eur. BP, 7647-14-5 0.008 g or USPWater for USP q.s. to 1.000 g +/− 0.002 g Injection *Diluted HClsolutions may be prepared from concentrated or fuming HCl or purchaseddirectly from a supplier.Viscosity

Viscosity will be varied using a viscosity modifier such as methylcellulose. The viscosity will be adjusted within a range spraycharacteristics at 10, 50, and 100 centipoise will be analyzed.

Preservative

The formulation in Table 1 will be modified by using 0.05% benzalkoniumchloride. The impact of surfactant on spray characteristics will beanalyzed.

Vasodilator

The formulation in Table 1 will be modified by the addition of avasodilator such as phentolamine at 20 mg/mL. The impact on spraycharacteristics will be analyzed.

Permeation Enhancer

The formulation in Table 1 will be modified by using a permeationenhancer such as 1% diethylene glycol monoethyl ether. The impact onspray characteristics will be analyzed.

Vitamin A

Formulation development will be conducted to support the addition of aLecithin, tween, or other suitable surfactant to solubilize vitamin Aand epinephrine, including varying the pH. Initial studies may be avisual color change after 5-7 days.

Compositions will be formulated and filled in a low O₂ environment.Nitrogen overlays and solution purges.

NaCl will be added to make 300 mosmol.

Compatibility with primary container components (glass and plunger) willbe investigated. Options for components in parallel will be assayed (forexample: different rubbers for plunger, plunger coatings, and/or glasssurface treatments).

Variation of pH at time of formulation and impact on stability will beinvestigated. Solutions at pH 4.0, 4.5, and 5.0 will be studied.

Stability studies at 25° C., 30° C., 40° C., and 50° C. will beconducted.

The formulations will be tested for potency, impurities, pH, andosmolality

Studies will be conducted for characterization of spray.

Stability

TABLE 2 Stability at 25° C., 30° C., and 40° C. 0 1 wk 3 wk 6 wk 10 wk16 wk 26 wk Primary Formulation 50 mg/mL A B A B A B A SecondaryFormulation 36 mg/mL A B A B A B A pH low A B A B A B A pH high A B A BA B A Configuration 2 A B A B A B A Configuration 3 A B A B A B A A =Assay, purity, pH, osmolality and spray characteristics. B = Assay andpurity

TABLE 3 Stability at 50° C. 0 1 wk 2 wk 3 wk 6 wk 10 wk PrimaryFormulation N/A B B B B AB pH low N/A B B B B A pH high N/A B B B B AConfiguration 2 N/A B B B B A Configuration 3 N/A B B B B A

Example 2: Preparation of Epinephrine Formulation 1

TABLE 4 Epinephrine Formulation 1 Amount Composition per spray ComponentCompendia (mg/mL) (mg/spray) (−) - Epinephrine USP 50.0 or 25.0 5.0 or2.5 Sodium metabisulfite EP, BP or 0.5 0.05 NF HCl* EP, BP or qs to pH4.7 +/− 0.3 USP/NF NaCl** USP 4.0 0.4  Purified Water USP qs *adjust pHto 4.7 ± 0.3 **target 300 mOsm

Epinephrine Formulation 1 was prepared by dissolving sodiummetabisulfite in Water for Injection, USP followed by the addition ofSodium Chloride, USP. Epinephrine, USP was added as a dry powder anddissolution of the epinephrine was aided by the addition of HCl until apH of 4.7 was achieved.

Example 3: Preparation of Epinephrine Formulation 2

TABLE 5 Epinephrine Formulation 2 Amount Composition per spray ComponentCompendia (mg/mL) (mg/spray) (−) - Epinephrine USP 50.0 or 25.0 5.0 or2.5 Sodium metabisulfite EP, BP or 0.5  0.05 NF HCl* EP, BP or qs to pH4.7 +/− 0.3 USP/NF NaCl** USP 4.0 0.4 Diethylene glycol NF 10.0  1.0monoethyl ether Sodium citrate NF 7.0 0.7 Hypromellose USP 1.0 0.1Purified Water USP qs *adjust pH to 4.7 ± 0.3 **target 300 mOsm

Water for Injection (˜20% of final formulation volume) was added to aclean dry beaker. Sufficient volume of a 10 mg/mL sodium metabisulfitesolution and an 80 mg/mL sodium chloride solution were added and mixedwell. Sufficient volumes of 10% solutions of each trisodium citrate,hypromellose and diethylene glycol monoethyl ether were added separatelyand mixed between additions. Epinephrine was added as a poorly solublepowder. 1.5M HCl was added slowly until nearly all epinephrine wasdissolved. 0.3M HCl was slowly added until a pH of 4.7+/−0.3 wasachieved. Water was added to bring the mixture to final volume.

Example 4: Preparation of Epinephrine Formulation 3

TABLE 6 Epinephrine Formulation 3 Amount Composition per spray ComponentCompendia (mg/mL) (mg/spray) (−) - Epinephrine USP 50.0 or 25.0 5.0 or2.5 Sodium metabisulfite EP, BP or 0.5  0.05 NF HCl* EP, BP or qs to pH4.7 +/− 0.3 AR USP/NF NaCl** USP 4.0 0.4 Diethylene glycol NF 10.0  1.0monoethyl ether Chlorobutanol NF 2.0 0.2 Sodium citrate NF 7.0 0.7Hypromellose USP 1.0 0.1 Purified Water USP AR AR *adjust pH to 4.7 ±0.3 **target 300 mOsm

Water for Injection (˜20% of final formulation volume) was added to aclean dry beaker. Sufficient volume of a 10 mg/mL sodium metabisulfitesolution and an 80 mg/mL sodium chloride solution were added and mixedwell. Sufficient volumes of 10% solutions of each trisodium citrate andhypromellose were added separately and mixed between additions.Separately, a solution of 10% diethelyene glycol monoethyl ether and 2%chlorobutanol was made in water. The diethylene glycol monoethylether/chlorobutanol solution was then added to the main mixing vesseland then mixed well. Epinephrine was added to the main mixing vessel asa poorly soluble powder. 1.5M HCl was added slowly until nearly allepinephrine was dissolved. 0.3M HCl was slowly added until a pH of4.7+/−0.3 was achieved. Water was added to bring the mixture to finalvolume.

Example 5: Preparation of Epinephrine Formulation 4

TABLE 7 Epinephrine Formulation 4 Amount Composition per spray ComponentCompendia (mg/mL) (mg/spray) (−) - Epinephrine USP 50.0 or 20.0 5.0 or2.0 Sodium metabisulfite EP, BP or 0.5  0.05 NF HCl* EP, BP or qs to pH4.7 +/− 0.3 AR USP/NF NaCl** USP 4.0 0.4 Diethylene glycol NF 10.0  1.0monoethyl ether Chlorobutanol NF 2.1  0.21 hemihydrate Citric acid NF4.2  0.42 monohydrate Hypromellose USP 1.0 0.1 Purified Water USP AR AR*adjust pH to 4.7 ± 0.3 **target 300 mOsm

Water for Injection (˜20% of final formulation volume) was added to aclean dry beaker. Sufficient volume of a 10 mg/mL sodium metabisulfitesolution and an 80 mg/mL sodium chloride solution were added and mixedwell. Sufficient volumes of 10% solutions of each citrate acidmonohydrate and hypromellose were added separately and mixed betweenadditions. Separately, a solution of 10% diethelyene glycol monoethylether and 2.1% chlorobutanol hemihydrate was made in water. Thediethylene glycol monoethyl ether/chlorobutanol hemihydrate solution wasthen added to the main mixing vessel and then mixed well. Epinephrinewas added to the main mixing vessel as a poorly soluble powder. 1.5M HClwas added slowly until nearly all epinephrine was dissolved. 0.3M HClwas slowly added until a pH of 4.7+/−0.3 was achieved. Water was addedto bring the mixture to final volume.

Example 6: In Vivo Study

Conscious animals that did not receive either a sedative or ananesthetic drug were used in the study. Prior to dosing, three electrodeleads were placed on the animal for the continuous monitoring of theheart rate and a standard electrocardiogram by the use of telemetry inwhich the signal from the electrode leads were transmitted to thereceiving unit by the use of Bluetooth. The cardiovascular parameterswere continuously recorded throughout the entire experiment. Inaddition, three blood samples were obtained from the veins in the frontlegs between 60 and 1-minute pre-dosing for the measurement of baselineplasma epinephrine levels. A specific dose of epinephrine (EpinephrineFormulation 2) was administered into the right nostril in each of sixanimals. The doses of epinephrine employed in these studies ranged from2 to 20 milligrams (mgs). The volume delivered was 100 microliters (uls)delivered in a 200 ul capacity cannula attached to a 100 ul calibratedpipette. There was no dead space in the cannula and the entire amountwas delivered at a depth of approximately ¾ inch into the nostril.Following the intranasal administration of epinephrine blood sampleswere obtained at 1, 5, 10, 15, 20, 30, 60 & 90 minutes post-dosing. Theblood samples were immediately kept on ice and the tubes werecentrifuged to separate the plasma from the heavier elements such as thered blood cells. Sodium metabisulfite was added to the plasma samples toprevent oxidation of epinephrine. The samples were stored at −70 degreesuntil they were analyzed by the use of an HPLC.

The average of the three pre-drug epinephrine samples was considered asthe baseline level. This was subtracted from the epinephrine levelsobtained at the specific time points ranging from 1-90 minutespost-dose. The resultant epinephrine concentrations expressed asnanograms/milliliter were considered to represent the absorption of theintranasal administration over time.

In a separate experiment, six animals received an intramuscularinjection of 0.3 mg of epinephrine administered into the upper quadrantof the left leg. Plasma samples were obtained at the same time points asthe intranasal experiments. The resultant plasma epinephrine time actioncurve was compared to those obtained by the intranasal administration.

The results of two experiments comparing the plasma levels observedfollowing the administration of either 5 mg or 10 mg administeredintranasally in comparison to the standard dose of 0.3 mg in the AdultEpiPen given by the intramuscular route are shown in FIG. 1 and FIG. 2.In all cases, the number of animals was six per group. As shown in FIG.1, the intranasal administration of 5 mg of epinephrine producedsignificantly higher plasma levels than those achieved with the EpiPenat the earliest time points of 1 and 5 minutes following drug delivery.In addition, the plasma concentrations of epinephrine were maintained atvirtually the same levels at the 30, 60 and 90 minute time periods. Atthese later time points, the levels of epinephrine resulting from theEpiPen administration had already significantly decreased from the peakobserved at 15 minutes. FIG. 2 shows the comparison of the plasmaepinephrine levels following the intranasal administration of 10 mg ascompared to the EpiPen. As shown in FIG. 2, the plasma levels ofepinephrine are much higher at the initial time periods of 1 and 5minutes following the intranasal dosage. Indeed, the plasma levelsachieved by the intranasal route of administration are higher than thoseobserved with the EpiPen throughout the entire 90 minutepost-administration.

Epinephrine is considered as the critical therapeutic treatment in acuteanaphylaxis following inadvertent exposure to a triggering agent, suchas nuts. This is a life threatening situation in which the rapidabsorption of epinephrine following administration is essential. As canbe seen in both FIG. 1 and FIG. 2, the intranasal delivery ofepinephrine produces higher plasma levels during the critical first fewminutes following exposure to the triggering agent than the EpiPen.Furthermore, the plasma levels of epinephrine remain elevated at higherlevels throughout the entire 90 minute time-action curve at the higherdose of 10 mg intranasal epinephrine compared to the EpiPen. This datasuggests that the intranasal route will provide for both a more rapidand more sustained treatment of the anaphylaxis. Finally, the plasmalevels following 10 mg are greater than those of 5 mg signifying adose-response relationship.

Example 7: A Study for Absorption of Intranasal Epinephrine Compared toConventional Intramuscular Epinephrine

The purpose of this study is to obtain pharmacokinetic data ofepinephrine administered via intranasal route (IN) and compare it withintramuscular (IM) route in healthy adult volunteers

Patients are reluctant to use Epipen® on emergency basis, perhapsbecause of improperly training, hesitancy and fear of needle. Otherroute of administration of epinephrine (EPI) may be more benefit such asintranasal route.

Primary outcome measures: Composite of Pharmacokinetics of epinephrine[Time Frame: predose, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180 minutespost-dose]

C_(max), Area Under Curve, T_(max) of epinephrine compare between 0.3 mgintramuscular and 5 mg intranasal route

Secondary outcome measures: Numbers of participants with adverse eventsas a measure of safety and tolerability [Time Frame: 1 year]

Study Design

-   -   Allocation: Non-Randomized (12 participants)    -   Intervention Model: Single Group Assignment    -   Masking: None (Open Label)    -   Primary Purpose: Treatment

Condition Anaphylaxis

-   -   Drug Epinephrine

Intervention

-   -   1. Intranasal epinephrine 5 mg/spray    -   2. Intramuscular epinephrine 0.3 mg    -   3. Intranasal saline spray    -   Other Name: adrenaline

Study Arms Experimental: epinephrine IN, epinephrine IM, saline IN

-   -   1. Intranasal saline    -   2. Intramuscular epinephrine    -   3. Intranasal epinephrine    -   Intervention: Drug Epinephrine

Example 8: Evaluation of Efficacy and Safety in Anaphylactic ReactionPatients

This study has three primary objectives:

-   -   (1) to compare the bioavailability of aqueous formulations to        that of hydro-alcoholic formulations of the company's        proprietary epinephrine nasal spray at two doses (3 mg and 6        mg);    -   (2) to compare the bioavailability of both formulations (aqueous        and hydro-alcoholic) to that of the standard intramuscular        injection—specifically, EpiPen® (0.30 mg); and    -   (3) to evaluate the effect of an intranasal allergen challenge        on the bioavailability of both intranasal epinephrine spray        formulations at both doses.

Secondarily, the study will evaluate the safety and tolerability of bothformulations at both doses

The study will enroll a total of 60 adult patients 18-45 years of age infive 12-patient cohorts at a single clinical site. To qualify forenrollment, all study patients will be confirmed to be healthy subjectswith a history of seasonal allergies; after enrollment, they will beexposed to an intranasal allergen at specific time points as part of theprotocol. Subjects who use current medication that interfere with resultof plasma epinephrine level (such as pseudoephedrine) will be excludedfrom the study.

Patients should not have had exposure to the epinephrine prior to thestudy entry. Patients must not have received treatment for theirallergies/anaphylaxis within 2 weeks of beginning the trial. Treatmentsinclude epinephrine I.V. or I.M. injections and/or immunotherapy.

All subjects are evaluated for safety and all blood collections forpharmacokinetic analysis are collected as scheduled. All studies areperformed with institutional ethics committee approval and patientconsent.

Example 9: Assessment of the Impact of Pre-existing Nasal Congestion onthe Systemic Absorption of Intranasally Administered Epinephrine inBeagle Dogs

This study evaluated epinephrine absorption during congestion or nocongestion and the effect of epinephrine on congestion followingaerosolized histamine exposure.

This study consisted of two dosing groups (Group 1—histamine and Group2—saline) with three male and three female beagle dogs per group(n=6/group). This study was conducted over four days (Study Days 0-3)with three dogs being tested per day. On Study Day (SD) 0 and SD 2,three dogs from Group 1 were anesthetized and administered a single doseof 5% histamine (dissolved in saline) via a nebulizer over a period of 5minutes. Epinephrine (4 mg/100 mL) was given in the same nostril, 15minutes post-histamine administration. On SD 1 and SD 3, three dogs fromGroup 2 were anesthetized and administered saline via a nebulizer over aperiod of 5 minutes. Epinephrine (4 mg/100 mL) was given in the samenostril, 15 minutes post-saline administration. A complete outline ofthe study design is provided in Table 8.

TABLE 8 Study Design Saline Administration of Sex Group Histamine (mL)Epinephrine Males Females 1 5% 0 4 mg IN into 3 3 congested nostril 2 0%0.4-0.7^(a) 4 mg IN into saline 3 3 exposed nostril ^(a)See Table 11 forindividual values

Epinephrine Formulation

Vehicle for the test article (epinephrine) was composed of sterile waterinjection containing 5 mg/10 mL of Na metabisulfite, 40 mg/10 mL ofsodium chloride, 0.7% trisodium citrate, 0.1% hypromellose, 0.05%chlorobutanol and 1% diethylene glycol monoethyl ether with a final pHof 5.0±0.5. For information regarding final concentration of eachchemical in the formulated test article, see Table 9.

TABLE 9 Test Article Formulation Compound Final Concentration Final pHEpinephrine  4 mg/100 μL 5.18 Sodium Chloride 0.4 mg/100 μL SodiumMetabisulfite 0.05 mg/100 μL  Trisodium citrate 0.7% Chlorobutanol 0.2%Hypromellose 0.1% Diethylene glycol   1% monoethyl ether

Intranasal Aerosol Delivery and Pressure Measurement System

A test system was designed and constructed for the intranasal deliveryof histamine and saline aerosols, and for measurement of nasalcongestion restriction in real time. The system and methods used aresimilar to those conducted by Tiniakov et. al, 2003. The systemdelivered aerosolized histamine at concentrations sufficient to elicitcongestion in the dog model via a conventional patient drug deliverynebulizer. A diagram of the congestion test system is depicted in FIG.3.

Histamine Nasal Exposures

Preceding each test, baseline ambient pressures of the test system atthe 3 L/min flow condition were recorded. The histamine generationnebulizer was filled with approximately 5 mL of 5% histamine solution or0.9% saline solution. The nebulizer was weighed prior to and after eachexposure to determine the generated histamine/saline (see Table 11).Dogs were anesthetized, and a cannula was lubricated with saline andinserted into the left nostril. The air flow was slowly increased toprovide 3 L/min of fresh air into the dog's nostril and pressuremeasurements were taken every five minutes while the cannula was inplace (see Table 10). Approximately 10 minutes post-cannula insertion,5% histamine (5 mg/mL) or 0.9% saline was administered via aerosol for 5minutes.

The nasal cannula was removed 5 minutes after cessation ofhistamine/saline administration (T=20 min) to facilitate the intranasaladministration of epinephrine. Approximately 10 min following theremoval of the nasal cannula, intranasal epinephrine (4 mg/100 μL) wasadministered (T=30 min). The nasal cannula was re-inserted into the nose60 min post-epinephrine administration (T=90 min). The cannula remainedin the nose for 40 minutes during which time nasal restriction pressureswere monitored. Blood draws were taken multiple times over the course ofeach test for analysis of epinephrine plasma levels in the histamine andsaline exposed dog groups. Table 10 shows the test matrix time course inminutes with the measurements/samples taken at each time point.

TABLE 10 Aerosol Exposure Test Matrix Epinephrine study minute time andtask test matrix T − 5 1^(st) blood draw T = 0 Insert nasal cannula &baseline ΔP reading T = 5 2^(nd) blood draw & nasal restriction ΔPreading T = 10 Histamine or saline aerosol start & nasal restriction ΔPreading T = 15 Histamine or saline aerosol stop & nasal restriction ΔPreading T = 20 Nasal restriction ΔP reading & removal of nasal cannula T= 25 3^(rd) blood draw T = 30 Epinephrine nasal administration T = 31,35, 40, 45, 50, 55, Blood draws 60, 90 T = 91, 100, 105, 110, 115Reinsert nasal cannula & nasal ΔP readings T = 120 Blood draw& nasalcannula ΔP readings T = 122, 124, 126, 128, 130 Nasal cannula ΔPreadings

Bioanalytical Analysis

Heart rate data was collected and recorded every 5 minutes throughoutthe experiment. Plasma samples were analyzed by liquid chromatographytandem-mass spectrometry (LC-MS/MS) using a C18-PFP column. LC-MS/MSanalysis was performed in positive electrospray ionization (ESI+) modeusing multiple reaction monitoring (MRM) ionization.

Pharmacokinetic Analysis

Epinephrine plasma concentrations were adjusted to account for theplasma epinephrine baseline by using average concentrations of the threepre-dose samples and subtracting that value from the post-dose valuesfor each dog. If baseline-subtraction resulted in negative values, thesesamples were assigned a value of zero. In addition, epinephrineconcentrations were considered as outliers and removed from analysis ifthey exceeded two times standard deviation from the mean ofbaseline-subtracted post-dose epinephrine plasma concentrations of eachanimal over the course of blood sampling (i.e., 1-90 min post-dose).

Histamine-Induced Nasal Congestion

Histamine administration induced congestion in all animals to varyingdegrees. The data was plotted to show the effect of histamine- andsaline-induced congestion effects following aerosol administration, andthe effect of epinephrine administration in reducing nasal congestion. Aplot including a pilot study with baseline histamine congestion results(leftmost bar at each time-point), histamine with epinephrineadministration test results (center bar), and saline with epinephrineadministration test results (rightmost bar) are shown in FIG. 4.

TABLE 11 Histamine-induced Congestion Nostril Cannula pressure (in H₂O)Nebulizer Test size^(b) Dog Pre- Post- Aerosol net use number (cm)ID/sex exposure^(c) exposure^(d) exposure (g) 1 (Pilot)^(a) 7.5 CPK/M0.530 0.714 Histamine NA 2 (Pilot)^(a) 6.5 CGV/F 0.730 1.626 Histamine0.63 3 (Pilot)^(a) 8 CXV/M 0.336 0.414 Histamine 0.56 1 8 CVL/M 0.6921.232 Histamine 0.43 2 8 CWZ/M 0.399 0.653 Histamine 0.43 3 9 CWT/M0.406 0.752 Histamine 0.43 4 7 CWP/F 0.460 0.433 Saline 0.63 5 7 CFI/F0.522 0.535 Saline 0.44 6 7 CSW/F 0.580 0.701 Saline 0.48 7 8 BCHG/F0.420 0.531 Histamine 0.44 8 7 CBC/F 0.735 3.411 Histamine 0.49 9 7.5CIH/F 0.606 2.372 Histamine 0.46 10 8 CXU/M 0.530 0.688 Saline 0.47 117.5 CUU/M 0.543 0.636 Saline 0.52 12 7.5 CYA/M 0.657 0.636 Saline 0.57^(a)Intranasal epinephrine not administered. ^(b)nostril measurementtaken as average of vertical and horizontal nostril diameters.^(c)pre-exposure nasal pressure taken 5 minutes after cannula insertioninto left nostril ^(d)nasal pressure taken at 5 minutes post aerosolexposure end

The average nasal pressure restriction levels in Groups 1 and 2, as wellas in the pilot study are plotted in FIG. 4. The restriction levels areshown at key time points: baseline, post-histamine/saline aerosoladministration, and post-epinephrine administration. The data indicate aprogressive increase in nasal congestion and flow restriction pressureat 5 and 10 minutes post-histamine exposure (Group 1). In contrast, noincrease in flow restriction pressure was observed following salineaerosol administration at these same time points. Epinephrine wasadministered via a micropipette in the left nostril 15 minutes followingthe cessation of histamine or saline aerosol administration. The dataindicate that epinephrine administration had a significant effect inreducing nasal congestion induced by histamine at the 60, 80, and 100minute time points with the nasal restriction pressures reduced tobaseline levels. This data shows that epinephrine has a significantanti-congestion effect. The pilot study data shows that withoutepinephrine administration, histamine induced congestion remainselevated at significant levels out to the 60, 80, and 100 minute timepoints.

Telemetry

Group 1 (5% Histamine+4 mg/100 μL Epinephrine)

Test article-related increases in heart rate were observed followingintranasal (IN) administration of epinephrine and typically stayed abovebaseline following epinephrine administration. The baseline heart rate(red line, FIG. 5) was set at 104 bpm based on the mean of the pre-dosemeasurements. A summary of the individual and mean heart rates of Group1 animals is provided in Table 12.

TABLE 12 Individual and Mean Heart Rates of Dogs in Group 1 - 5%Histamine + 4 mg/100 μL Epinephrine Histamine (Group 1) individual andmean heart rates (bpm) Mean Event/Time(min) CVL CWZ CWT BCHG CBC CIHMean STDEV BD/−5 114 105 124 80 118 85 104 18.1 Insert Cannula/0 112 111113 85 120 83 104 15.8 ΔP, BD/5 112 113 115 85 122 87 106 15.6 ΔP,saline start/10 112 122 108 84 129 88 107 18.0 ΔP, saline stop/15 NA 143126 84 143 99 119 26.6 ΔP, Pull Cannula/20 119 135 124 83 143 95 11723.2 BD/25 105 134 123 84 148 104 116 23.2 Epinephrine 30 115 126 112 84145 121 117 20.0 BD/1 115 126 116 75 134 123 115 20.7 BD/5 146 139 12075 195 119 132 39.4 BD/10 153 143 114 79 201 96 131 44.1 BD/15 137 146118 81 197 94 129 41.5 BD/20 127 141 117 86 203 99 129 41.3 BD/25 117132 119 90 207 93 126 42.7 BD/30 116 139 119 89 205 127 133 39.2 BD/60116 134 117 90 168 154 130 28.3 Re-insert Cannula 61 116 133 114 93 155147 126 23.1 ΔP, 70 123 140 117 107 154 147 131 18.4 ΔP, 75 124 143 113111 142 151 131 17.0 ΔP, 80 121 142 116 107 144 150 130 17.6 ΔP, 85 117146 116 102 144 149 129 19.8 ΔP, BD, 90 120 143 114 103 137 146 127 17.4ΔP, 92 121 146 117 100 129 146 127 17.8 ΔP, 94 120 147 117 99 141 139127 18.3 ΔP, 96 123 147 115 99 133 145 127 18.5 ΔP, 98 132 147 117 99137 142 129 17.9 ΔP, 100 153 148 112 99 136 140 131 21.3

Group 2 (Saline+4 mg/100 μL Epinephrine)

Test-article related increases in HR were noted in Group 2 (FIG. 6), butthe pattern was significantly different from Group 1. The baseline heartrate (red line, FIG. 6) was set at 97 bpm based on the mean of thepre-dose measurements. While the initial changes in HR (pertaining tostabilizing the anesthetic plane) were present in Group 2, an evidentincrease in HR was not observed until 30-60 minutes post-epinephrineadministration. This mirrors the rise in epinephrine blood plasma levelsin Group 1, but with a delayed effect in Group 2 at the 30-60 minutemark (this is discussed further, below). Once the HR increased in Group2 animals, it typically remained elevated until the end of theexperiment. A summary of the individual and mean heart rates of Group 2animals is provided in Table 13.

TABLE 13 Individual and Mean Heart Rate of Dogs in Group 2 - Saline + 4mg/100 μL Epinephrine Saline (Group 2) individual and mean heart rate(bpm) Mean Event/Time(min) CWP CFI CSW CXU CVU CYA Mean STDEV BD/−5 9480 102 106 95 107 97 10.1 Insert Cannula/0 95 89 101 120 95 108 101 11.2ΔP, BD/5 96 92 99 123 88 101 100 12.3 ΔP, saline start/10 95 98 109 12680 100 101 15.3 ΔP, saline stop/15 95 99 108 125 83 99 102 14.1 ΔP, PullCannula/20 86 102 109 128 85 95 101 16.2 BD/25 93 103 116 121 85 94 10214.1 Epinephrine 30 94 105 118 114 88 95 102 12.0 BD/1 100 108 109 96 9196 100 7.2 BD/5 97 107 113 93 93 90 99 9.1 BD/10 94 107 108 94 96 97 996.4 BD/15 91 109 107 99 100 96 100 6.7 BD/20 91 111 106 103 102 91 1018.1 BD/25 90 113 107 104 103 93 102 8.7 BD/30 99 115 107 109 104 98 1056.4 BD/60 92 137 127 137 103 104 117 19.4 Re-insert Cannula 61 91 133127 131 114 108 117 16.2 ΔP, 70 88 136 127 138 134 115 123 19.1 ΔP, 7591 132 120 140 136 115 122 18.1 ΔP, 80 88 132 115 138 138 114 121 19.4ΔP, 85 96 133 108 138 136 116 121 17.2 ΔP, BD, 90 95 132 102 138 137 116120 18.6 ΔP, 92 96 132 99 136 134 113 118 18.1 ΔP, 94 96 129 105 136 133116 119 16.2 ΔP, 96 96 133 109 139 136 118 122 17.1 ΔP, 98 118 139 113135 137 125 128 10.8 ΔP, 100 135 158 118 145 142 135 139 13.3

Pharmacokinetic Results

Plasma samples were collected at the indicated time points and analyzed.Plasma epinephrine concentration profiles over time are plotted forindividual animals within a group (FIG. 8, FIG. 9). AUC, T_(max) andC_(max) were calculated using post-dose baseline-subtracted epinephrineconcentrations for each individual animal and the trapezoid rule (Tables14-15).

TABLE 14 AUC and C_(max) of epinephrine in dogs from Group 1 Group 1Parameter^(a) BCHG CBC CIH CVL CWT CMZ Average SD Dose, mg 4 4 4 4 4 4 —— T_(max), min 1 25 5 1 5 1 6 9 C_(max), mg/mL 1.4 3.4 4.0 7.2 2.2 2.93.5 2.1 AUC₁₋₉₀ min, 42 194 182 109 106 68 117 61 ng/mL · min^(a)Abbreviations: C_(max), maximum plasma concentration before baselinesubtraction; T_(max), time to reach C_(max); AUC_(1-90 min), area underthe plasma concentration time curve from time 1 min to 90 min afterbaseline subtraction

TABLE 15 AUC and C_(max) of epinephrine in dogs from Group 2 Group 2Parameter^(a) CFI CSW CUU CWP CXU CYA Average SD Dose, mg 4 4 4 4 4 4 —— T_(max), min 90 60 90 90 1 90 70 36 C_(max), mg/mL 0.8 1.1 1.4 0.9 4.81.4 1.7 1.5 AUC_(1-90 min), 33 83 71 478 67 56 59 18 ng/mL · min^(a)Abbreviations: Cmax, maximum plasma concentration before baselinesubtraction; T_(max), time to reach C_(max); AUC_(1-90 min), area underthe plasma concentration time curve from time 1 min to 90 min afterbaseline subtraction

In Tables 14 and 15, plasma concentration vs. time data were firstanalyzed for the individual animal and then PK measurements (AUC,C_(max), T_(max)) from the individual animals were averaged within agroup.

Furthermore, group average epinephrine concentration profiles over timeare plotted for the two study groups (FIG. 10). AUC, T_(max) and C_(max)calculated using the trapezoid rule are shown in Table 16.

TABLE 16 AUC, T_(max) and C_(max) of epinephrine after administration indogs (average plasma concentrations from all dogs in the same group)Study - congestion vs saline Group 1 - Congestion Group 2 - SalineParameter^(a,b), unit (4 mg x 1 nostril) (4 mg x 1 nostril) Dose, mg 4 4T_(max), min 1 90 C_(max), ng/mL 2.9 1.2 AUC_(1-last), ng/mL · min 11760 t_(1/2) NC NC ^(a)Abbreviations: C_(max), maximum plasmaconcentration before baseline subtraction; T_(max), time to reachC_(max); AUC_(1-90 min), area under the plasma concentration time curvefrom time 1 min to 90 min after baseline subtraction; NC, not calculateddue to pre-dose concentration higher than post-dose concentration offailed to establish elimination phase. ^(b)Values were obtained from NCAby WinNonlin (Build 8.1.0.3530)

In Table 16, plasma concentration vs. time data were first averaged forall animals within the same group and then PK measurements were obtainedfrom the averaged data. As compared to values reported in Tables 14 and15 where individual T_(max) varied from one animal to another, thisresulted in different T_(max) and C_(max) values between the two typesof analyses (Tables 14/15 vs Table 16). AUC, on the other hand, remainedessentially same for both of these analyses.

In the congestion model (Table 16), the T_(max) was 1 min vs 90 min forthe congested dogs vs the saline dogs, respectively. The C_(max) was 2.9ng/mL vs 1.2 ng/mL for the congested dogs vs the saline dogs,respectively. Finally, the AUC was 117 ng/mL-min vs 60 ng/mL-min for thecongested dogs vs the saline dogs, respectively. For all of theseaforementioned values, an IN dose of epinephrine at 4 mg/100·L wasadministered to the same nostril where either histamine (congested dogs)or saline (control) was previously administered. Clearly, theepinephrine when delivered intranasally to the congested dogs wasabsorbed faster, leading to higher plasma levels as compared to dogswith no congestion that received saline alone. This was an unexpectedand surprising result since the assumption would be that dogs withcongestion would have constricted nasal passageways that reduceabsorption efficiency. Upon further investigation, it is noted thatBleske et al. demonstrated in dogs that epinephrine plasma levels,following intranasal administration, were enhanced by the concomitantintranasal administration of the alpha blocker, phentolamine. Theexplanation was that phentolamine prevented the epinephrine inducedvasoconstriction thus increasing the mucosal absorption of epinephrine.Nasal congestion associated with allergy is due to the release ofhistamine from mast cells which causes a profound vasodilation in thenasal tissue. Therefore, it is likely that the histamine inducedvasodilation offset the vasoconstrictive properties of the intranasalepinephrine resulting in enhanced absorption. Finally, there was adifference in heart rate levels in the congested, epinephrineadministered dogs as compared to the saline epinephrine administrationwhere the heart rates were clearly elevated, due to increased plasmaepinephrine levels in the congested dogs versus the saline administereddogs.

To determine if nasal congestion affects the systemic absorption of INadministered epinephrine, Student's t-test was first used to compareAUC, T_(max) and C_(max) between two study groups (FIG. 11). The Group 1and Group 2 AUC and C_(max) were not significantly different whereas theT_(max) of the Group 1 animals was significantly lower than that of theGroup 2 animals.

Furthermore, bioequivalence was assessed using Ln-transformed AUC,C_(max) and T_(max) of individual animals (Table 17). Bioequivalence isdefined as when the 90% confidence intervals [CI] of the geometric meanratio between the test (Group 1—Congestion) and reference (Group2—Saline) fall within 80-125%. Results show that intranasal (IN)administered epinephrine does not demonstrate bioequivalence betweenGroup 1 and Group 2 animals, as ratios deviate from 100% and CI (90%)values fall well outside of the 80-125% range. In addition,bioequivalence analysis indicates that the study is under-powered (Power<80%), likely due to large inter-individual variability and small numberof animals in each group.

TABLE 17 Bioequivalence analysis of epinephrine after a single IN doseto saline (reference) and congestion (test) dogs NCA PK Ratio ofgeometric mean Power of Study at Parameter^(a,b), unit (% of reference)90% CI 20% (80/20 Rule)^(b) Dose, mg per animal 4 T_(max), min 7.41.4-3.9 0.107 C_(max), ng/mL 217 115-408 0.151 AUC_(1-last), 180 109-2960.182 ng/mL · min ^(a)Abbreviations: C_(max), maximum plasmaconcentration before baseline subtraction; T_(max), time to reachC_(max); AUC_(0-∞), area under the plasma concentration time curve fromtime 0 min to infinite time; CI, confidence interval. ^(b)the power todetect a difference in least square means equal to 20% of the referenceleast squares mean and the desired result is that the power is greaterthan 0.8 or 80%.

Blood samples were collected up to 35 min prior to and up to 90 min postdrug administration to determine epinephrine plasma concentrations (seeTable 18). The results show that a spike in epinephrine plasmaconcentration was often achieved within 1 or 5 minutes of intranasaladministration.

TABLE 18 Epinephrine plasma concentration. Determined Animal Dose AmountCollection Matrix Conc. ID Sex (mg) Time (min) (ng/mL) CVL M 4 Pre 350.148 CVL M 4 Pre 25 0.192 CVL M 4 Pre 5  0.347 CVL M 4  1 7.469 CVL M 4 5 5.314 CVL M 4 10 1.595 CVL M 4 15 1.192 CVL M 4 20 0.883 CVL M 4 250.786 CVL M 4 30 1.139 CVL M 4 60 1.076 CVL M 4 90 0.96  CWZ M 4 Pre 35ND CWZ M 4 Pre 25 0.139 CWZ M 4 Pre 5  0.161 CWZ M 4  1 3.002 CWZ M 4  51.137 CWZ M 4 10 0.843 CWZ M 4 15 0.773 CWZ M 4 20 1.092 CWZ M 4 251.213 CWZ M 4 30 0.852 CWZ M 4 60 0.74  CWZ M 4 90 0.83  CWT M 4 Pre 35ND CWT M 4 Pre 25 0.125 CWT M 4 Pre 5  0.493 CWT M 4  1 1.153 CWT M 4  52.465 CWT M 4 10 0.976 CWT M 4 15 1.091 CWT M 4 20 1.211 CWT M 4 251.378 CWT M 4 30 1.387 CWT M 4 60 1.605 CWT M 4 90 1.663 BCHG F 4 Pre 350.147 BCHG F 4 Pre 25 0.147 BCHG F 4 Pre 5  0.144 BCHG F 4  1 1.507 BCHGF 4  5 0.736 BCHG F 4 10 0.405 BCHG F 4 15 0.697 BCHG F 4 20 0.718 BCHGF 4 25 0.503 BCHG F 4 30 0.445 BCHG F 4 60 0.527 BCHG F 4 90 0.846 CBC F4 Pre 35 ND CBC F 4 Pre 25 ND CBC F 4 Pre 5  ND CBC F 4  1 2.171 CBC F 4 5 1.459 CBC F 4 10 1.81  CBC F 4 15 1.833 CBC F 4 20 1.731 CBC F 4 253.385 CBC F 4 30 1.926 CBC F 4 60 1.839 CBC F 4 90 3.313 CIH F 4 Pre 35ND CIH F 4 Pre 25 ND CIH F 4 Pre 5  ND CIH F 4  1 2.801 CIH F 4  5 3.969CIH F 4 10 1.014 CIH F 4 15 1.099 CIH F 4 20 1.144 CIH F 4 25 1.04  CIHF 4 30 1.694 CIH F 4 60 2.356 CIH F 4 90 2.439 CWP F 4 Pre 35 ND CWP F 4Pre 25 ND CWP F 4 Pre 5  0.125 CWP F 4  1 0.575 CWP F 4  5 0.512 CWP F 410 0.385 CWP F 4 15 0.686 CWP F 4 20 0.721 CWP F 4 25 0.463 CWP F 4 300.415 CWP F 4 60 0.682 CWP F 4 90 1.067 CFI F 4 Pre 35 0.263 CFI F 4 Pre25 0.418 CFI F 4 Pre 5  0.327 CFI F 4  1 0.407 CFI F 4  5 0.545 CFI F 410 0.427 CFI F 4 15 0.44  CFI F 4 20 0.453 CFI F 4 25 0.5  CFI F 4 300.799 CFI F 4 60 0.642 CFI F 4 90 1.141 CSW F 4 Pre 35 0.147 CSW F 4 Pre25 0.127 CSW F 4 Pre 5  0.166 CSW F 4  1 0.577 CSW F 4  5 0.82  CSW F 410 0.927 CSW F 4 15 0.761 CSW F 4 20 0.922 CSW F 4 25 0.867 CSW F 4 301.133 CSW F 4 60 1.202 CSW F 4 90 1.166 CXU M 4 Pre 35 0.461 CXU M 4 Pre25 ND CXU M 4 Pre 5  ND CXU M 4  1 5.229 CXU M 4  5 3.036 CXU M 4 101.009 CXU M 4 15 0.787 CXU M 4 20 0.856 CXU M 4 25 0.906 CXU M 4 300.703 CXU M 4 60 0.801 CXU M 4 90 1.969 CUU M 4 Pre 35 ND CUU M 4 Pre 250.263 CUU M 4 Pre 5  0.317 CUU M 4  1 0.32  CUU M 4  5 0.434 CUU M 4 100.662 CUU M 4 15 0.749 CUU M 4 20 0.789 CUU M 4 25 0.881 CUU M 4 30 0.9 CUU M 4 60 1.222 CUU M 4 90 1.729 CYA M 4 Pre 35 ND CYA M 4 Pre 25 0.234CYA M 4 Pre 5  0.732 CYA M 4  1 0.433 CYA M 4  5 0.903 CYA M 4 10 0.422CYA M 4 15 0.872 CYA M 4 20 0.917 CYA M 4 25 0.781 CYA M 4 30 0.9  CYA M4 60 1.125 CYA M 4 90 1.92

Example 10: Assessment of Whether Epinephrine Crosses the Blood BrainBarrier

Pre- and post-IN epinephrine (4 mg/0.1 mL IN) samples of plasma and CSFwere collected at just prior to pre-dose (0 min) and 15 min post-dosefor the study in Example 9. Blood samples were processed to plasma;plasma and CSF samples were stabilized. Samples were assayed forepinephrine levels.

As shown in FIG. 12, pre- and post-dose plasma levels of epinephrinewere at a pre-dose average of 0.214 ng/mL and at 15 min post-epinephrinelevels were 1.123 ng/mL. For both pre- and post-dose time points, noepinephrine was detected in CSF (see Table 19).

TABLE 19 Epinephrine blood plasma concentration. Matrix Dose AmountCollection Concentration Animal ID Sex (mg) Time and Type (ng/mL) CVX M4 Pre-CSF ND CVX M 4 15 min CSF ND CVX M 4 Pre-Plasma 0.360 CVX M 4 15min Plasma 1.060 CWD M 4 Pre-CSF ND CWD M 4 15 min CSF ND CWD M 4Pre-Plasma 0.276 CWD M 4 15 min Plasma 0.369 CWP F 4 Pre-CSF ND CWP F 415 min CSF ND CWP F 4 Pre-Plasma 0.218 CWP F 4 15 min Plasma 2.151 BCHGF 4 Pre-CSF ND BCHG F 4 15 min CSF ND BCHG F 4 Pre-Plasma ND BCHG F 4 15min Plasma 0.910

The IN administration of epinephrine to dogs did not result in detectionof epinephrine in CSF samples at 15 min post-dose administration, whileplasma levels did increase at this same time point. Therefore, INadministration of epinephrine to dogs does not result in epinephrinecrossing the blood brain barrier.

Example 11—A GLP Pharmacokinetic Comparison of Intranasal Application vsCurrent Therapeutic Approach in Beagle Dogs

In this GLP study, which was based on previous studies that optimizedthe pharmacokinetics (PK) of intranasal epinephrine in terms of deliveryand dose selection, the down-selected dose was tested for a PKassessment as a primary endpoint in dogs with heart rate also assessedto demonstrate the effect of epinephrine on the cardiovascular system.

The epinephrine formulation was composed of sterile injection watercontaining 5 mg/10 mL of Na metabisulfite, 40 mg/10 mL of sodiumchloride, 0.7% Trisodium citrate, 0.1% hypromellose, 0.2% chlorobutanoland 1% Diethylene glycol monoethyl ether with a final pH of 5.0±0.5.Epinephrine was included at the concentrations as shown in Table 20. Forinformation regarding vendor, lot number, and final concentration ofeach chemical in the formulated test formulation, see Table 20.

TABLE 20 Chemicals Used in Test Formulation Lot Compound Vendor NumberFinal Concentration (−) Epinephrine Spectrum 2HD0281 4 mg/100 μl(Group 1) 5 mg/100 μl (Group 2) Sodium Spectrum 1FIO675  0.4 mg/100 μLChloride Sodium Spectrum 1GC1002 0.05 mg/100 μL Metabisulfite TrisodiumSigma BCBV1682 0.7% citrate Hypromellose Sigma SLBR5196V 0.1% DiethyleneSigma O4508HEV   1% glycol monoethyl ether Chlorobutanol Spectrum1FF0469 0.2% Hydrochloric Spectrum 2GJ0228 NA Acid Sterile waterSpectrum A1705131 NA for Injection

Two dosing concentrations (4 mg/100 μL and 5 mg/100 μL) were formulated2 times during the course of this study. Complete information regardingthe date of formulation, batch ID associated with each formulated testarticle, amount of epinephrine (grams) used in each formulation, and thefinal pH of each formulated test article used for dose administrationare included in Table 21.

TABLE 21 Test Article Formulation Batches Dose Amount of Dose Date ofConcentration Epinephrine Final Study Concentration Formulation(Pre-dose) used pH Day (Post-Dose) Aug. 21, 2018 4.4 mg/100 μL 0.8008 g5.207 16-17 4.4 mg/100 μL Aug. 21, 2018 5.4 mg/100 μL 1.0033 g 5.20216-17 5.4 mg/100 μL Aug. 31, 2018 4.1 mg/100 μL 0.8004 g 4.729 29-30 4.0mg/100 μL Aug. 31, 2018 5.3 mg/100 μL 1.0010 g 4.814 29-30 5.1 mg/100 μL

The EpiPen® Auto-Injector 0.3 mg (Mylan Specialty, L.P., USP Grade) wasutilized as a control article in this study. Individual EpiPens® wereprocured from local pharmacies and stored at room temperature (20°-25°C.) protected from light.

A total of 48 dogs participated in this study with 16 dogs (8/sex) pertreatment group. Table 22 outlines the study design.

TABLE 22 Study Design Epinephrine Sex Group (mg) Total AdministrationRoute Male Female 1 4 mg in 100 μl volume IN via pipette tip into 8 8 ofvehicle the right nostril 2 5 mg in 100 μl volume IN via pipette tipinto 8 8 of vehicle the right nostril 3 0.3 mg in 0.3 mL IM singleinjection to 8 8 (EpiPen ® Adult) thigh muscle

Two dogs/sex/group received a single administration of either INepinephrine at 4 mg or 5 mg (Groups 1 and 2) or a single EpiPen® IMinjection (Group 3) on Study Days 0, 1, 16, and 17. Note that individualdogs within each group were only dosed a single time during the courseof this study.

Telemetry measurements were collected from all animals during thetreatment phase of this study. Prior to dose administration, telemetriccollection jackets were placed on animals. Data collection pointsoccurred 60 min prior to dose administration (baseline) through the 120minute endpoint for a total collection time of 180 min. The parametersthat were evaluated included: EKG (PR, QRS, QT, and RR; a continuouscollection). Heart rate values were collected prior to doseadministration at 60, 12, and 2-3 minutes before epinephrineadministration and at the following intervals post-epinephrineadministration: 1, 5, 10, 15, 20, 25, 30, 60, 90, and 120 minutes. A sixsecond EKG was reported at the C_(max) for epinephrine for each dog toevaluate the EKG parameters listed above.

Approximately 2 mL of whole blood was collected at the following timepoints: prior to dosing (60, mins, 15 mins, 2-3 mins pre-dose) and at 1,5, 10, 15, 20, 25, 30, 60, 90, and 120 mins post-dose administration(±10% of target time point).

Prior to PK data analysis, the three prior to dosing time points (60mins, 15 mins, 2-3 mins pre-dose) epinephrine plasma values for each dogwere averaged, then this average subtracted from the post-doseepinephrine plasma values reported at time points 1, 5, 10, 15, 20, 25,30, 60, 90 and 120 mins post-dose administration for all animals onstudy. Should one or more of the pre-dose samples fall beneath the limitof quantification (BLQ), the mean of the remaining quantifiable valueswas used for baseline correction. If all three pre-dose samples fellunder the limit of detection (i.e., values not determined), no baselinecorrection was performed on the post-dose samples. If, after baselinecorrection, the post-dose values are negative (i.e., >0) these valueswere changed to 0 for subsequent PK analysis.

Pharmacokinetic (PK) data analysis and evaluation of plasmaconcentration-time curves was performed. Individual epinephrine plasmaconcentration time profiles from epinephrine treated animals wereanalyzed using model-independent methods. Pharmacokinetic parameterswere obtained for each animal following a single intranasaladministration of epinephrine to animals in Groups 1 and 2 or followinga single IM injection of epinephrine to animals in Group 3.Concentrations less than the lower limit of quantitation (LLOQ<0.4ng/mL) were set to 0 for pharmacokinetic analysis.

For each animal, the following pharmacokinetic parameters weredetermined: maximum observed plasma concentration (C_(max)), time ofmaximum observed plasma concentration (T_(max)), and area under theplasma concentration time curve (AUC). The AUC from time 0 to 120minutes (AUC_(0-120min)) and the AUC from time 0 to infinity (AUC_(INF))were calculated by the linear trapezoidal method for all animals with atleast 3 consecutive quantifiable concentrations. For Day 1, 0 was usedas an estimate of the 0 hr concentration. Half-life values (T_(1/2))were reported for each plasma concentration time profile that hadsufficient plasma concentrations in the terminal elimination phase (atleast 3 samples not including Tmax), an adjusted R² of ≥0.9, and weredetermined from at least 3 half-lives of data. Additionalpharmacokinetic parameters calculated were clearance divided by fractionof dose absorbed (Cl/F), volume of distribution divided by the fractionof dose absorbed (Vz/F), and mean residence time (MRTlast). The femaleto male exposure ratio (F:M) was calculated for each dose group usingthe following formula: F:M=Mean AUC_(0-120 min Female)÷MeanAUC_(0-120 min Male)

The % AUC extrapolated (% AUCExtrap) was calculated as: %AUCExtrap=[(AUC_(INF)−AUC_(Tlast))/AUC_(INF)]×100

Group 1-4 mg IN Epinephrine

Test formulation-related increases in heart rate were observed followingintranasal (IN) administration of Epinephrine (4 mg) on Study Day (SD)0-1 and SD 16-17. All animals were administered IN Epinephrine (4 mg,100 μL) via a cannula. The mean heart rate through time of all animalsdosed with 4 mg epinephrine is provided in FIG. 13.

On SD 16-17, heart rates increased following dose administration withthe max heart rate measurement (181 bpm) occurring 25 min post-dose. At120 min post-dose the heart rate of 2 animals had returned to a normalbaseline range while the heart rates of the remaining 6 animals remainedelevated (Table 23).

On SD 29-30, heart rates increased following dose administration withthe max heart rate measurement (226 bpm) occurring 15 min post-dose. At120 min post-dose the heart rate of seven dogs had returned to a normalbaseline range while the heart rate of one animal remained elevatedslightly above the baseline value (Table 23).

TABLE 23 Individual and Mean Heart Rate of Dogs in Group 1-4 mg INEpinephrine Individual and Mean Heart Rates (bpm) - 4 mg IN EpinephrineStudy Days 16-17 Time CVR CLB CWB CNB CWD CXX CWZ CYN Mean −60 137 155111 146 90 154 134 109 130 −12 117 135 117 154 160 139 129 106 132 −2102 152 81 151 108 170 119 92 122 1 106 144 166 156 85 135 125 115 129 5157 137 105 156 125 144 136 119 135 10 116 158 123 164 116 151 122 126135 15 124 163 117 143 129 131 130 99 130 20 137 146 98 130 76 142 128114 121 25 120 174 87 145 126 181 118 132 135 30 122 157 83 158 115 138137 153 133 60 171 159 119 122 153 127 153 117 140 90 97 157 112 155 105135 124 127 127 120 74 129 140 139 108 121 150 141 125 Study Days 29-30Time CGR ACHG CPK CBC CUD CFU CUE CJE Mean −60 181 92 106 131 106 132111 135 124 −12 139 141 130 141 109 95 83 138 122 −2 117 99 98 123 13595 57 103 103 1 132 125 120 126 142 114 119 128 126 5 122 126 113 135158 105 154 118 129 10 182 156 113 146 97 95 119 130 130 15 226 100 101138 134 103 65 135 125 20 116 122 118 129 168 72 77 126 116 25 119 120112 139 144 76 73 121 113 30 150 134 112 140 162 112 86 114 126 60 114122 94 137 98 125 93 128 114 90 222 99 91 131 86 85 67 99 110 120 89 10088 125 76 71 70 97 90

Group 2-5 mg IN Epinephrine

Test article-related increases in heart rate were observed followingintranasal (IN) administration of Epinephrine (5 mg) on Study Day (SD)0-1 and SD 16-17. All animals were administered IN Epinephrine (5 mg,100 μL) via a cannula. The mean heart rate through time of all animalsdosed with 5 mg epinephrine is provided in FIG. 14.

On SD 16-17, heart rates increased following dose administration withthe max heart rate measurement (174 bpm) occurring 60 min post-dose. At90 min post-dose the heart rates of all 8 animals had returned to anormal baseline range (Table 24).

On SD 29-30, heart rates increased following dose administration withthe max heart rate measurement (220 bpm) occurring 1 min post-dose. At120 min post-dose the heart rates of five animals had returned to anormal baseline range while the heart rates of three animals remainedelevated above the normal baseline range (Table 24).

TABLE 24 Individual and Mean Heart Rate of Dogs in Group 2-5 mg INEpinephrine Individual and Mean Heart Rates (bpm)-5 mg IN EpinephrineStudy Days 16-17 Min CVL CSW CVX CTZ CWT CWF CXV CGF Mean −60 93 128 138158 103 112 119 149 125 −12 163 118 129 152 104 145 116 124 131 −2 65128 73 145 86 133 104 124 107 1 121 126 120 151 129 113 100 137 125 5146 141 88 132 111 131 129 146 128 10 145 130 128 144 105 130 123 128129 15 135 132 140 147 95 140 122 113 128 20 147 145 122 129 137 124 130137 134 25 115 139 121 139 124 109 138 135 128 30 168 128 125 123 128101 118 136 128 60 174 133 149 134 139 102 124 128 135 90 120 109 105118 113 120 90 117 112 120 92 108 125 113 84 105 116 109 107 Study Days29-30 Time CNE BCHG CRA CTZ CUF CIH CUU CRF Mean −60 146 108 127 142 85133 122 116 122 −12 126 132 135 137 96 116 115 151 126 −2 126 72 127 11084 133 99 122 109 1 181 140 220 119 91 122 102 142 140 5 172 109 153 123103 173 113 119 133 10 144 109 143 125 113 156 106 118 127 15 125 113160 114 111 130 109 124 123 20 125 100 149 127 101 114 106 149 121 25129 84 142 117 98 130 104 119 115 30 113 133 155 120 116 133 103 112 12360 130 92 122 97 108 127 86 96 107 90 106 92 124 128 73 140 133 127 115120 105 90 125 129 63 116 88 142 107

Group—EpiPen® 0.3 mg IM Injection

Intramuscular (IM) injection of EpiPen® 0.3 mg resulted in overallincreased heart rates in all animals. All animals were administered anEpiPen® 0.3 mg IM injection on the right hind leg. The mean heart ratethrough time of all animals dosed with EpiPen® Adult is provided in FIG.15.

On SD 16-17, heart rates increased following dose administration withthe max heart rate measurement (222 bpm) occurring 20 min post-dose.Consistent with results from SD 0-1, the heart rates of all eight dogsremained elevated above the normal baseline range at 120 min post doseadministration (Table 25).

On SD 29-30, heart rates increased following dose administration withthe max heart rate measurement (222 bpm) occurring 20 min post-dose.Consistent with results from SD 0-1, the heart rates of all eight dogsremained elevated above the normal baseline range at 120 min post doseadministration (Table 25).

TABLE 25 Individual and Mean Heart Rate of Dogs in Group 3 - EpiPen ®0.3 mg Injection Individual and Mean Heart Rates (bpm) - EpiPen ® 0.3 mgInjection Study Days 16-17 Min CWU CHT CXU CLZ CYA CPL CYR CPN Mean −60112 122 121 117 152 106 106 110 118 −12 124 87 100 87 107 109 153 149115 −2 105 145 123 111 135 83 85 107 112 1 123 194 143 147 157 133 174108 147 5 142 144 144 103 172 137 148 112 138 10 182 137 157 127 124 153112 147 142 15 169 148 127 121 101 153 119 124 133 20 222 145 158 107157 153 179 151 159 25 212 167 142 120 144 156 157 134 154 30 205 144190 154 131 191 147 176 167 60 160 186 211 144 148 180 188 162 172 90151 173 199 204 159 178 165 151 173 120 163 151 193 123 153 167 151 145156 Study Days 29-30 Time CPJ CBE CTE CEU CUT CFI CUZ CGV Mean −60 61113 124 103 66 73 80 84 88 −12 71 130 127 113 70 120 112 82 103 −2 121108 108 98 74 73 96 91 96 1 104 156 127 125 94 151 107 89 119 5 115 132107 113 86 162 110 109 117 10 103 131 138 116 178 107 161 103 130 15 142131 136 137 134 184 93 103 133 20 166 136 138 139 163 124 108 118 137 25165 139 140 146 155 113 98 111 133 30 179 175 122 142 192 130 110 125147 60 154 173 130 179 201 148 129 146 158 90 155 182 151 173 189 179144 125 162 120 155 182 114 151 162 132 154 133 148

Pharmacokinetic Analysis

All epinephrine plasma concentrations were baseline corrected forendogenous epinephrine levels using the mean predose concentrations;therefore, the following discussion of epinephrine systemic exposure isbased on the data in excess of endogenous levels.

Systemic exposure to epinephrine was independent of sex. There were noconsistent differences in individual plasma concentration time profiles,C_(max), and AUC values between males and females (the F:M AUC_(0-24hr)ratios following intranasal administration were 0.711 and 1.20 forGroups 1 and 2, respectively, and the F:M AUC_(0-24hr) ratio followingintramuscular administration was 1.27 for Group 3); therefore, thefollowing discussion is based on data for males and females combined.

The variability in mean epinephrine plasma concentrations, as measuredby CV values, ranged from 53.4% to 170% following a single INadministration of epinephrine to dogs in Groups 1 and 2 and from 48.7%to 174% following a single IM injection of 0.3 mg epinephrine to dogs inGroup 3. Epinephrine was quantifiable up to 120 minutes post-dose forGroup 1 (4 mg), up to 30 or 120 minutes post-dose for Group 2 (5 mg),and up to 120 minutes post-dose for Group 3 (0.3 mg). Individual peakepinephrine plasma concentrations were observed between 1 and 30 minutespost-dose for Group 1 (4 mg), between 1 and 90 minutes post-dose forGroup 2 (5 mg), and between 5 and 60 minutes post-dose for Group 3 (0.3mg).

Following a single IN administration of epinephrine to dogs, meanC_(max) and AUC_(0-120min) values for epinephrine increased slightlywith increasing dose from 4 to 5 mg. A 1.25-fold increase in epinephrinedose resulted in an approximate 1.22-fold increase in mean epinephrineC_(max) values (2.48 and 3.01 ng/mL at 4 and 5 mg, respectively) and anapproximate 1.09-fold increase in mean epinephrine AUC_(0-120min) values(75.0 and 81.8 min*ng/mL at 4 and 5 mg, respectively). Following asingle IM injection of 0.3 mg epinephrine to dogs, mean C_(max) andAUC_(0-120min) values for epinephrine were 2.76 ng/mL and 110 min*ng/mL,respectively.

Mean MRT_(last) values for epinephrine following IN administration were51.1 and 53.9 minutes at 4 and 5 mg, respectively. The mean MRT_(last)value for epinephrine following IM injection was 50.4 minutes. Acomplete summary of the pharmacokinetic aforementioned pharmacokineticparameters are provided in Table 26.

Overall, the individual plasma concentration-time profiles weregenerally similar between animals treated with epinephrine via INadministration when compared to animals treated with epinephrine via IMinjection (FIG. 16).

TABLE 26 Epinephrine Pharmacokinetic Parameters Following a Single INAdministration of 4 or 5 mg Epinephrine or a Single IM Injection of 0.3mg Epinephrine to Dogs (Males and Females Combined) Dose C_(max)C_(max)/Dose T_(max) ^(a) T_(last) ^(a) AUC_(0-120 min)AUC_(0-120 min)/Dose MRT_(last) Group Route (mg) Statistic (ng/mL)(ng/mL/mg) (min) (min) (min*ng/mL) (min*ng/mL/mg) (min) 1 IN 4 N 16 1616 16 16 16 16 Mean 2.48 0.619 20 120  75.0 18.7 51.1 SD 2.27 0.568(1-30) (120-120) 53.8 13.5 11.3 CV % 91.7 91.7 NA NA 71.8 71.8 22.2 2 IN5 N 16 16 16 16 15 15 15 Mean 3.01 0.602 15 120  81.8 16.4 53.9 SD 2.960.592 (1-90)  (30-120) 46.3 9.26 12.9 CV % 98.3 98.3 NA NA 56.6 56.623.8 3 IM 0.3 N 16 16 16 16 16 16 16 Mean 2.76 9.22 25 120  110 365 50.4SD 2.78 9.25 (5-60) (120-120) 42.1 140 9.39 CV % 100 100 NA NA 38.4 38.418.6 NA—Not applicable. ^(a)Median (minimum-maximum), median value onlyreported if actual collection interval.

Three groups of 8 male and 8 female Beagle dogs each were administered 4mg/100 μL IN epinephrine to the right nostril (Group 1), 5 mg/100 μL INepinephrine to the right nostril (Group 2), or 0.3 mg in 0.3 mL EpiPen®(adult) IM to the thigh muscle (Group 3), followed by timed blood drawsfor this PK study. Additionally, dogs were telemetrized to monitor theirheart rate pre- and post-dose administration.

Heart rate data was comparable in the 4 and 5 mg IN Group 1 and 2(respectively) dogs with an increase in mean heart rate occurring atapproximately 5-10 min post-dose in Group 1 dogs and at approximately 1min post-dose in Group 2 dogs. The peak increase in mean heart rate was132 bpm at 10 min and 132 bpm at 1 min post-IN administration for Group1 and 2 dogs, respectively. The heart rate in the Group 3 EpiPen®administered dogs began to increase at 1 min post-dose with a peakincrease in mean heart rate (167 bpm) occurring at approximately 90 minpost-dose administration.

Systemic exposure to epinephrine was independent of sex. Individual peakepinephrine plasma concentrations were observed between 1 and 30 minutespost-dose for Group 1 (4 mg), between 1 and 90 minutes post-dose forGroup 2 (5 mg), and between 5 and 60 minutes post-dose for Group 3 (0.3mg). Following a single IN administration of epinephrine to dogs, meanC_(max) and AUC_(0-120min) values for epinephrine increased slightlywith increasing dose from 4 to 5 mg. A 1.25-fold increase in epinephrinedose resulted in an approximate 1.22-fold increase in mean epinephrineC_(max) values (2.48 and 3.01 ng/mL at 4 and 5 mg, respectively) and anapproximate 1.09-fold increase in mean epinephrine AUC_(0-120min) values(75.0 and 81.8 min*ng/mL at 4 and 5 mg, respectively). Following asingle IM injection of 0.3 mg epinephrine to dogs, mean C_(max) andAUC_(0-120min) values for epinephrine were 2.76 ng/mL and 110 min*ng/mL,respectively.

Mean MRT_(last) values for epinephrine following IN administration were51.1 and 53.9 minutes at 4 and 5 mg, respectively. The mean MRT_(last)value for epinephrine following IM injection was 50.4 minutes.

Overall, the individual plasma concentration-time profiles weregenerally similar between animals treated with epinephrine via INadministration when compared to animals treated with epinephrine via IMinjection.

Example 12—Dose Administration of Epinephrine Via One or Two Nostrils

This study investigated intranasal administration of Epinephrine in aBeagle dogs to evaluate if one or two nostril administrations ofepinephrine produces the optimal plasma levels.

The epinephrine formulation used is defined in Table 27. The studyconsisted of three male and three female beagle dogs per group (Table28). Groups 1-4 were administered epinephrine through a 100 μlintranasal device intranasally. Following dose administration, allanimals had serial blood samples collected for pharmacokinetic analysis.

TABLE 27 Test Article Formulation Final Compound Concentration Final pHEpinephrine   5 mg/100 μl 5.35 Sodium Chloride  0.4 mg/100 μl Sodium0.05 mg/100 μl Metabisulfite Trisodium citrate 0.7% Hypromellose 0.1%Diethylene glycol   1% monoethyl ether Epinephrine   10 mg/100 μl 4.90Sodium Chloride  0.4 mg/100 μl Sodium 0.05 mg/100 μl MetabisulfiteTrisodium citrate 0.7% Hypromellose 0.1% Diethylene glycol   1%monoethyl ether

TABLE 28 Study Design Total Dose Level Dose (mg) of Volume NostrilGroups Epinephrine (μl) Administration Males Females 1  5 100 One 3^(a)3^(a) 2 10 (two nostrils 100 Both 3^(b) 3^(b) with 5 mg/nostril) 3 10100 One 3^(a) 3^(a) 4^(c) 20 (two nostrils 100 Both 3^(b) 3^(b) with 10mg/ nostril)

264 PK samples total from Groups 1, 2, 3, and 4 were analyzed by liquidchromatography tandem-mass spectrometry (LC-MS/MS) using a C18-PFPcolumn. LC-MS/MS analysis was performed in positive electrosprayionization (ESI+) mode using multiple reaction monitoring (MRM)ionization.

Epinephrine plasma concentrations were baseline-subtracted using averageconcentrations of the three pre-dose samples. If baseline-subtractionresulted in negative values, these samples were assigned a value ofzero. In some cases (e.g., low dose groups 1 and 3), post-doseepinephrine concentrations of several animals were all below pre-dosebaseline concentrations. In addition, epinephrine concentrations wereconsidered as outliers if they exceeded two times standard deviationfrom the mean of baseline-subtracted post-dose epinephrine plasmaconcentrations of each animal over the course of blood sampling (i.e.,1-90 min post-dose).

AUC, Tmax and Cmax were calculated using the trapezoid rule (GraphPadPrism 7.0c) and the post-dose baseline-subtracted outlier-removedepinephrine concentrations for each individual animal (Tables 29-32).

TABLE 29 AUC and Cmax of epinephrine in dogs from group 1 (5 mg × 1nostril) Group 1 (5 mg × 1 nostrils) Parameter, unit 1 2 3 4 5 6 AverageSD Dose, mg 5 5 5 5 5 5 Cmax, ng/mL NC NC 0.1 0.7 0.1 NC 0.3 0.3 Tmax,min NC NC 90 90 7 NC 62 48 AUC1-90 min, NC NC 2 13 6 NC 7 6 ng/mL*min

TABLE 30 AUC and Cmax of epinephrine in dogs from group 2 (5 mg × 2nostril) Group 2 (5 mg × 2 nostrils) Parameter, unit 1 2 3 4 5 6 AverageSD Dose, mg 10 10 10 10 10 10 Cmax, ng/mL 1.4 1.7 4.2 2 4.7 0.3 2.4 1.7Tmax, min 15 10 90 22 5 30 29 31 AUC1-90 min, 23 38 117 76 166 5 71 62ng/mL*min

TABLE 31 AUC and Cmax of epinephrine in dogs from group 3 (10 mg × 1nostril) Group 3 (10 mg × 1 nostrils) Parameter, unit 1 2 3 4 5 6Average SD Dose, mg 10 10 10 10 10 10 Cmax, ng/mL NC NC 8.7 0.8 NC NC4.8 5.6 Tmax, min NC NC 12 85 NC NC 51 54 AUC1-90 min, NC NC 378 20 NCNC 199 253 ng/mL*min

TABLE 32 AUC and Cmax of epinephrine in dogs from group 4 (10 mg × 2nostril) Group 4 (10 mg × 2 nostrils) Parameter, unit 1 2 3 4 5 6Average SD Dose, mg 20 20 20 20 20 20 Cmax, ng/mL 2.8 3.1 2.5 2 6.7 3.43.4 1.7 Tmax, min 60 15 10 90 63 90 55 35 AUC1-90 min, 178 96 80 62 241151 135 68 ng/mL * min

Example 13—an Intranasal and Intramuscular Dose Range-FindingAdministration of Epinephrine in Beagle Dogs

This study investigated intranasal administration of Epinephrine atvarious dose levels in a Beagle dogs. In addition, the Adult and JREpi-Pens were administered via intramuscular injection to providepharmacokinetic profiles for comparison.

The epinephrine formulation used is defined in Table 33. The studyconsisted of three male and three female beagle dogs per group (Table34). Groups 1-4 were administered 100 μl of epinephrine at varyingconcentrations. Dose formulation was administered intranasally using acannula. Groups 5 and 6 were administered epinephrine via intramuscularinjection using and Adult EpiPen or Jr. EpiPen, respectively. Followingdose administration, all animals had serial blood samples collected.

TABLE 33 Test Article Formulation Compound Final Concentration Final pHEpinephrine   5 mg/100 μl 4.94 Sodium Chloride  0.4 mg/100 μl SodiumMetabisulfite 0.05 mg/100 μl Trisodium citrate 0.7% Hypromellose 0.1%Diethylene glycol   1% monoethyl ether Epinephrine   10 mg/100 μl 4.85Sodium Chloride  0.4 mg/100 μl Sodium Metabisulfite 0.05 mg/100 μlTrisodium citrate 0.7% Hypromellose 0.1% Diethylene glycol   1%monoethyl ether Epinephrine   20 mg/100 μl 4.50 Sodium Chloride  0.4mg/100 μl Sodium Metabisulfite 0.05 mg/100 μl Trisodium citrate 0.7%Hypromellose 0.1% Diethylene glycol   1% monoethyl ether

TABLE 34 Study Design Total Dose Dose Level (mg) Volume AdministrationGroups of Epinephrine (μl) Route Males Females 1 10 100 Nostril, Both3^(a) 3^(a) 2 20 100 Nostril, One 3^(b) 3^(b) 3  5 100 Nostril, One3^(a) 3^(a) 4 10 100 Nostril, One 3^(b) 3^(b) 5 Adult EpiPen 300 IM3^(a) 3^(a) (0.3) 6 Jr EpiPen 300 IM 3^(b) 3^(b) (0.15)

PK samples were analyzed by liquid chromatography tandem-massspectrometry (LC-MS/MS) using a C18-PFP column. LC-MS/MS analysis wasperformed in positive electrospray ionization (ESI+) mode using multiplereaction monitoring (MRM) ionization.

AUC, Tmax and Cmax were calculated using the trapezoid rule (GraphPadPrism 7.0c) and the post-dose baseline-subtracted outlier-removedepinephrine concentrations for each individual animal (Tables 35-40).For Groups 5 and 6 (EpiPen groups), AUC, Tmax and Cmax were alsocalculated using the post-dose baseline-subtracted epinephrineconcentrations (without removing outliers) for comparison (number inparentheses in Tables 39 and 40).

TABLE 35 AUC and Cmax of epinephrine in dogs from group 1 (10 mg × 2nostril) Parameter, Group 1 (10 mg × 2 nostrils) unit 1 2 3 4 5 6Average SD Dose, mg 20 20 20 20 20 20 Cmax, 1.8 7.2 2.2 3.2 6.8 7.4 4.82.7 ng/mL Tmax, min 1 5 60 60 90 90 51 40 AUC1- 59 249 72 134 284 485214 161 90 min, ng/mL * min

TABLE 36 AUC and Cmax of epinephrine in dogs from group 2 (10 mg × 1nostril) Parameter, Group 2 (10 mg × 1 nostrils) unit 1 2 3 4 5 N/AAverage SD Dose, mg 20 20 20 20 20 Cmax, 15.7 53 4.7 32.3 10.8 23.3 19.5ng/mL Tmax, 5 5 1 60 5 15 25 min AUC1- 769 1875 201 1700 495 1008 742 90min, ng/mL * min

TABLE 37 AUC and Cmax of epinephrine in dogs from group 3 (5 mg × 1nostril) Parameter, Group 3 (5 mg × 1 nostrils) unit 1 2 3 4 5 6 AverageSD Dose, mg 5 5 5 5 5 5 Cmax, 1.3 3.5 2.7 6 3 4.1 3.4 1.6 ng/mL Tmax,min 90 5 30 30 5 90 42 39 AUC1- 67 185 117 177 131 205 147 51 90 min,ng/mL * min

TABLE 38 AUC and Cmax of epinephrine in dogs from group 4 (10 mg × 1nostril) Parameter, Group 4 (10 mg × 1 nostrils) unit 1 2 3 4 5 6Average SD Dose, mg 10 10 10 10 10 10 Cmax, 4.1 13.9 5.7 10.6 17.8 2.49.1 6 ng/mL Tmax, min 28 5 15 15 4 10 13 9 AUC1- 228 339 94 259 491 85249 154 90 min, ng/mL * min

TABLE 39 AUC and Cmax of epinephrine in dogs from group 5 (EpiPen Adult0.3 mg IM) Group 5 (EpiPen Adult 0.3 mg IM) Parameter, unit 1 2 3 4 5 6Average SD Dose, mg 0.3 0.3 0.3 0.3 0.3 0.3 Cmax, ng/mL 1.4 3 1.6 1.32.1 (4.1) 7.5 2.8 (3.1) 2.4 (2.4) Tmax, min 60 60 30 15 10 (14) 15 32(32) 23 (22) AUC1-90 min, 94 158 101 62 111 (123) 193 120 (122) 47 (47)ng/mL * min

TABLE 40 AUC and Cmax of epinephrine in dogs from group 6 (EpiPen Junior0.15 mg IM) Group 6 (EpiPen Junior 0.15 mg IM) Parameter, unit 1 2 3 4 56 Average SD Dose, mg 0.15 0.15 0.15 0.15 0.15 0.15 Cmax, ng/mL 0.9 1.1(2.5) 1.2 (3.8) 2.2 (4.6) 1.1 1.1 (3.0) 1.3 (2.7) 0.5 (1.4) Tmax, min 1 5 (10) 60 (20) 10 (5)  20 30 (20) 21 (13) 22 (9)  AUC1-90 min, 33 56(65)  77 (101) 50 (63) 74 66 (80) 59 (69) 16 (22) ng/mL * min

Example 14—an Intranasal Low Dose Range-Finding Administration ofEpinephrine in Beagle Dogs

This is a study investigating intranasal administration of Epinephrineat various dose levels and dosing intervals in Beagle dogs. This non-GLPPK study utilized the Adult EpiPen® administered via intramuscularinjection to provide a pharmacokinetic profile for comparison.

The plasma levels and heart rate changes produced by intranasaladministration of increasing epinephrine concentrations (2 mg/100 μL, 3mg/100 μL, and 4 mg/100 μL) were assessed (Groups 1-3). In addition,plasma epinephrine concentrations and changes in heart rate wereassessed following intranasal administration of 2 doses of epinephrine(4 mg/100 μL) in the same or opposite nostril (Group 4 and Group 8B)with a 20 minute interval between doses. Dual intramuscular injection ofthe EpiPen® Adult 0.3 mg with a 20 minute interval between doses wasused for pharmacokinetic comparison (Group 5/8A).

Serial blood samples were collected for bioanalytical andpharmacokinetic (PK) analysis and several pre- and post-dose timepoints.

Part I—Assessment of Plasma Epinephrine Concentration Following 2 mg, 3mg, and 4 mg Intranasal Epinephrine Administration

Each group in Part I of Study 4 consisted of three male and three femaledogs (n=six/group). Each dog was administered one dose of epinephrine inthe right nostril using a cannula. An overview of the Part I StudyDesign is provided in Table 41. Plasma samples were obtained at thefollowing time points post-epinephrine administration: 1, 5, 10, 15, 20,30, 60 & 90 minutes.

TABLE 41 Study Design Dose Epinephrine Volume Nostril Group (mg) perDose (μl) Administration Administration Males Females 1 2 100 One IN 3A3A 2 3 100 One IN 3B 3B 3 4 100 One IN 3C 3C

Vehicle for the test article was composed of sterile injection watercontaining 5 mg/10 mL of Na metabisulfite, 40 mg/10 mL of sodiumchloride, 0.7% trisodium citrate, 0.1% hypromellose, 0.2% chlorobutanoland 1% Diethylene glycol monoethyl ether with a final pH of 5.0±0.5 (seeTable 42).

TABLE 42 Test Article Formulation Compound Final Concentration Final pHEpinephrine   2 mg/100 μl 5.30 Sodium Chloride  0.4 mg/100 μl SodiumMetabisulfite 0.05 mg/100 μl Trisodium citrate 0.7% Chlorobutanol 0.2%Hypromellose 0.1% Diethylene glycol   1% monoethyl ether Epinephrine   3mg/100 μl 5.08 Sodium Chloride  0.4 mg/100 μl Sodium Metabisulfite 0.05mg/100 μl Trisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1%Diethylene glycol   1% monoethyl ether Epinephrine   4 mg/100 μl 5.32Sodium Chloride  0.4 mg/100 μl Sodium Metabisulfite 0.05 mg/100 μlTrisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1% Diethyleneglycol   1% monoethyl ether

Epinephrine plasma concentrations were adjusted to account for theplasma epinephrine baseline by using average concentrations of the threepre-dose samples and subtracting that value from the post-dose valuesfor each dog. If baseline-subtraction resulted in negative values, thesesamples were assigned a value of zero. In addition, per the sponsor'sinstruction, epinephrine concentrations were considered as outliers andremoved from analysis if they exceeded two times standard deviation fromthe mean of baseline-subtracted post-dose epinephrine plasmaconcentrations of each animal over the course of blood sampling (i.e.,1-90 min post-dose).

TABLE 43 AUC and Cmax of epinephrine in dogs from Group 1 Parameter,Group 1 (2 mg × 1 nostril) unit 1 2 3 4 5 6 Average SD Dose, g 2 2 2 2 22 — — T_(max), min 1 60 90 1 60 1 36 39 C_(max), ng/mL 1.0 0.7 6.2 0.65.1 2.8 2.7 2.4 AUC_(1-90 min), 47 43 237 13 209 25 96 100 ng/mL · min

TABLE 44 AUC and Cmax of epinephrine in dogs from Group 2 Parameter,Group 2 (3 mg × 1 nostril) unit 1 2 3 4 5 6 Average SD Dose, g 3 3 3 3 33 — — T_(max), min 90 5 1 15 5 5 20 35 C_(max), ng/mL 0.7 1.5 8.2 0.23.4 0.3 2.4 3.1 AUC_(1-90 min), 25 64 227 14 167 18 86 90 ng/mL · min

TABLE 45 AUC and Cmax of epinephrine in dogs from Group 3 Parameter^(a),Group 3 (4 mg × 1 nostril) unit 1 2 3 4 5 6 Average SD Dose, g 4 4 4 4 44 — — T_(max), min 60 60 1 20 60 90 49 32 C_(max), ng/mL 2.9 1.7 2.1 2.212.2 1.4 3.7 4.2 AUC_(1-90 min), 84 112 98 88 688 59 188 246 ng/mL · min

Three doses of epinephrine, 2, 3, and 4 mg IN (100 μL volume each) wereevaluated and the lowest dose compared to the PK and heart rate resultsof the EpiPen Jr. The Cmax of the 2, 3, and 4 were 2.7, 2.4 and 3.7ng/mL, respectively while the AUC was 96, 86, and 188 ng/mL·min,respectively. It appears that the two lower doses of IN epinephrineexhibited similar pharmacokinetics, while the higher dose of 4 mg INincreased in a dose-dependent manner.

The 2 mg/100 μL dose, produced comparable epinephrine plasma levels tothe EpiPen® Junior. Lastly, the 4 mg IN epinephrine PK results werecomparable to the adult EpiPen® PK results (EpiPen® results reported inStudy 3 as compared to 4 mg IN PK values from Group 3 of this report;Cmax values of 3.7 and 2.8 ng/mL and AUC of 188 and 120 ng/mL·min forthe 4 mg IN vs EpiPen®, respectively). Most importantly, the 4 mg INepinephrine resulted in an elevated plasma concentration much faster(within 1 min post-dose administration) as compared to the EpiPen IMadministration, where plasma epinephrine concentrations did not begin toincrease until 5-10 min post-administration.

Part II: Assessment of Plasma Epinephrine Concentration FollowingRepeated Intranasal Administration of 4 mg Epinephrine

This study compared the plasma levels and heart rate changes observedfollowing a second dose of epinephrine administered either intranasallyor intramuscularly 20 minutes following the first dose. One potentialpitfall of repeated intranasal dosing is that the first intranasaladministration may result in intense vasoconstriction of the nasalepithelium thus significantly and adversely impacting the absorption ofthe second dose. Therefore, this study also evaluated this possibilityby administering the second intranasal dose of epinephrine in theopposite nostril. Similar to the first intranasal paradigm (2 doses,same nostril), repeated intramuscular injection of the EpiPen® was usedfor pharmacokinetic comparison.

Groups 4 and 5 consisted of three dogs/sex (n=six/group) while Group 8Aconsisted of one dog/sex (n=2 dogs) and Group 8B consisted of two dogsper sex (n=4 dogs). Each dog in Group 4 and 8B was administered twodoses of epinephrine (4 mg/100 μL) with a 21 min interval between doses.All intranasal doses were administered using a cannula. Dose 1 wasadministered in the right nostril followed by a second intranasal dosein the right (Group 4, same nostril) or left (Group 8B, oppositenostril) nostril. Dogs in Group 5 and 8A were administered twointramuscular injections of the EpiPen® Adult (0.3 mg) with a 21 mininterval between injections. Injections were administered in oppositethighs with the first dose being administered in the right thigh and thesecond dose being administered in the left thigh. A complete overview ofthe study design is provided in Table 46.

TABLE 46 Study Design Dose Epinephrine Volume Nostril Group (mg) perDose (μl) Administration Administration Males Females 4 4 + 4 100 + 100Twice (same IN 3 3 nostril) 5 1 Adult 300 + 300 — IM, one in each 3 3EpiPen ® (0.3) + thigh muscle 1 Adult EpiPen ® (0.3) 8A 1 Adult 300 +300 — IM, one in each 1 1 EpiPen ® (0.3) + thigh muscle 1 Adult EpiPen ®(0.3) 8B 4 + 4 100 + 100 Twice (opposite IN 2 2 nostril)

The test article used was formulated as described in Part I of thisstudy (see Table 47). The EpiPen® Adult (0.3 mg) Auto-injector was usedas a control article for pharmacokinetic comparison in this part.

TABLE 47 Test Article Formulation Compound Final Concentration Final pHEpinephrine   4 mg/100 μl 5.04² Sodium Chloride  0.4 mg/100 μl 5.18³Sodium Metabisulfite 0.05 mg/100 μl Trisodium citrate 0.7% Hypromellose0.1% Diethylene glycol   1% monoethyl ether ²Formulation for Groups 4,6, and 7 ³Formulation for Group 8B

Epinephrine plasma concentrations were adjusted for each dog's plasmaepinephrine baseline by using average concentrations of the threepre-dose samples and subtracting that average from the subsequentpost-dose plasma epinephrine values. If this adjustment resulted innegative values, these samples were assigned a value of zero. Inaddition, epinephrine concentrations were considered as outliers andremoved from analysis if they exceeded two times standard deviation fromthe mean of baseline-subtracted post-dose epinephrine plasmaconcentrations of each animal over the course of blood sampling (i.e.,1-120 min post-dose).

AUC, Tmax and Cmax were calculated using the trapezoid rule (GraphPadPrism 7.0c) and post-dose baseline-subtracted outliers-removedepinephrine concentrations for each individual animal (Tables 48-50).

For Group 5/8A, the elimination phase could be defined, therefore theAUC, T_(max), C_(max), and half-life (t_(1/2)) were also calculatedusing NCA for comparison (AUC=740 ng/mL·min; T_(max)=30 min; C_(max)=15ng/mL; t_(1/2)=38 min).

TABLE 48 AUC and Cmax of epinephrine in dogs from Group 5 and Group 8AParameter, Group 5 (EpiPen ® Adult 0.3 mg × 2 injections) unit 1 2 3 4 56 CRA¹ CXX¹ Average SD Dose, g 0.3 + 0.3 0.3 + 0.3 0.3 + 0.3 0.3 + 0.30.3 + 0.3 0.3 + 0.3 0.3 + 0.3 0.3 + 0.3 — — T_(max), min 10 30 10 30 2530 30 60 28 16 C_(max), ng/mL 17.0 22.7 9.9 27.3 54.9 24.5 3.2 5.0 20.616.6 AUC_(1-90 min), 713 737 785 1067 1218 1014 208 375 765 343 ng/mL ·min ¹Animals run in Group 8A.

TABLE 49 AUC and Cmax of epinephrine in dogs from Group 4 Parameter,Group 4 (4 mg × 2 doses × 1 nostril) Aver- unit 1 2 3 4 5 6 age SDDose,g 4 + 4 4 + 4 4 + 4 4 + 4 4 + 4 4 + 4 — — T_(max), min 60 10 60 525 25 31 24 C_(max), ng/mL 2.3 2.6 38.1 18.6 1.5 1.2 10.7 15.0AUC_(1-90 min), 107 88 1324 811 50 62 407 537 ng/mL · min

TABLE 50 AUC and Cmax of epinephrine in dogs from Group 8B Parameter,Group 8B (4 mg × 2 doses × 2 nostrils) unit 1 2 3 4 — — Average SD Dose,g 4 + 4 4 + 4 4 + 4 4 + 4 — — — — T_(max), min 90 1 25 60 — — 44 39C_(max), ng/mL 2.6 2.7 3.1 6.5 — — 3.7 1.9 AUC_(1-90 min), 161 135 151372 — — 205 112 ng/mL · min

The plasma levels and heart rate changes were evaluated following asecond dose of epinephrine administered either intranasally (to the samenostril), intranasally (in opposite nostrils) or intramuscularly 21minutes following the first dose. As compared to a single dose ofepinephrine at 4 mg IN (see part 1 Group 3) the Cmax and AUC of theGroup 4 dogs (two IN doses of epinephrine in the same nostril) was 10.7ng/mL and 407 ng/mL·min, respectively. The two EpiPen® doses alsodelivered 21 min apart also resulted in higher Cmax and AUC of 20.6ng/mL and 765 ng/mL·min as compared to a single dose.

Example 15—Stability Testing of Pharmaceutical Spray Formulations

The pharmaceutical spray formulation was quantified and monitored byhigh pressure liquid chromatography (HPLC). The impurities detectedinclude epinephrine sulfonic acid, adrenochrome, norepinephrine, andadrenalone. The following Tables 51-58 show the test results forepinephrine spray formulations at varying dosages, storage temperatures,and storage lengths.

TABLE 51 20 mg/mL or 2 mg/dose pH 4.7, 0.5% Chlorobutanol at 5 C., 25C., and 40 C. Time points (months) Specification 5 C. 25 C. 40 C. Test(Stability) T0 T = 2.27 T = 1 T = 1 pH 4.2-5.2 4.614 4.593 4.615 4.607Osmolality 300-500 mOsm/kg 394 403 405 Weight Loss Max ≤2.2%, 0.00% Av≤1.1% Assay  95.0%-110.0% 95.85% 97.47% 96.44% 96.35% Epinephrine NMT9.0% 0.46% 0.20% 1.09% 3.69% Sulfonic Acid Adrenochrome NMT 0.5% 0.08%0.05% 0.11% 0.23% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT3.0% ND ND ND ND Total Impurities ≤12.0% 0.60% 0.44% 1.44% 4.17%Enantiomeric 99.14% 99.19% 99.01% Purity Chlorobutanol  3.94 mg/mL AssaySodium 0.345 mg/mL 0.206 mg/mL 0.014 mg/mL Metabisulfite Assay

TABLE 52 60 mg/mL or 6 mg/dose pH 4.7, 0.5% Chlorobutanol at 5 C., 25C., and 40 C. Time points (months) Specification 5 C. 25 C. 40 C. Test(Stability) T0 T = 1.6 T = 1 T = 1 pH 4.2-5.2 4.644 4.649 4.622 4.585Osmolality 600-1000 mOsm/kg 797 790 793 Weight Loss Max ≤2.2%, Av ≤1.1%Assay  95.0%-110.0% 100.60% 100.80% 100.60% 98.60% Epinephrine NMT 3.0%0.42% 0.20% 0.81% 1.74% Sulfonic Acid Adrenochrome NMT 0.2% 0.06% ND ND0.05% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 1.2% ND ND NDND Total Impurities ≤12.0% 0.54% 0.30% 0.95% 2.38% Enantiomeric 99.01%99.77% 98.42% Purity Chlorobutanol 4.41 mg/mL Assay Sodium .019 mg/mL.013 mg/mL ND Metabisulfite Assay

TABLE 53 20 mg/mL or 2 mg/dose pH 4.7, 0.2% Chlorobutanol at 25 C.Specification Time points (days), 25 C. Test (Stability) T0 28 56 84 pH4.662 4.587 4.591 4.545 Osmolality 428 Assay 95.0%-110.0% 101.55% 97.58%99.05% 98.51% Epinephrine NMT 3.0% 0.00% 1.05% 1.74% 2.08% Sulfonic AcidAdrenochrome NMT 0.5% 0.09% 0.22% 0.36% 0.53% Norepinephrine NMT 4.0% NDND ND ND Adrenalone NMT 3.0% ND ND ND ND Total Impurities ≤12.0% 0.34%1.70% 2.29% 3.30% Chlorobutanol 1.56 mg/mL 1.46 mg/mL 1.36 mg/mL 1.37mg/mL Assay

TABLE 54 20 mg/mL or 2 mg/dose pH 4.7, 0.2% Chlorobutanol at 40 C.Specification Time points (days), 40 C. Test (Stability) T0 28 56 84 pH4.662 4.556 4.537 4.474 Osmolality 428 Assay 95.0%-110.0% 101.55% 97.90%97.31% 96.96% Epinephrine NMT 3.0% 0.00% 2.52% 2.65% 2.57% Sulfonic AcidAdrenochrome NMT 0.5% 0.09% 0.45% 0.41% 0.43% Norepinephrine NMT 4.0% NDND ND ND Adrenalone NMT 3.0% ND ND ND 0.47% Total Impurities ≤12.0%1.27% 3.76% 3.86% 4.41% Chlorobutanol 1.56 mg/mL 1.25 mg/mL 1.16 mg/mL1.07 mg/mL Assay

TABLE 55 50 mg/mL or 5 mg/dose pH 4.7, 0.2% Chlorobutanol at 25 C.Specification Time points (days), 25 C. Test (Stability) T0 28 56 84 pH4.667 4.63 4.598 4.525 Osmolality 689 Assay 95.0%-110.0% 101.69% 98.46%98.73% 99.61% Epinephrine NMT 3.0% 0.29% 0.85% 1.08% 1.07% Sulfonic AcidAdrenochrome NMT 0.5% 0.04% 0.13% 0.17% 0.18% Norepinephrine NMT 4.0% NDND ND ND Adrenalone NMT 3.0% ND ND ND ND Total Impurities ≤12.0% 0.47%1.09% 1.73% 2.01% Chlorobutanol 1.55 mg/mL 1.47 mg/mL 1.36 mg/mL 1.35mg/mL Assay

TABLE 56 50 mg/mL or 5 mg/dose pH 4.7, 0.2% Chlorobutanol at 40 C.Specification Time points (days), 40 C. Test (Stability) T0 28 56 84 PH4.667 4.586 4.524 4.47 Osmolality 689 Assay 95.0%-110.0% 101.69% 100.14%97.42% 98.92% Epinephrine NMT 3.0% 0.29% 1.19% 1.34% 1.19% Sulfonic AcidAdrenochrome NMT 0.5% 0.04% 0.17% 0.10% 0.15% Norepinephrine NMT 4.0% NDND ND ND Adrenalone NMT 3.0% ND ND ND 0.05% Total Impurities ≤12.0%0.47% 2.45% 2.54% 3.53% Chlorobutanol 1.55 mg/mL 1.25 mg/mL 1.08 mg/mL1.07 mg/mL Assay

TABLE 57 6 mg/mL or 6 mg/dose pH 4.7, 0.2% Chlorobutanol at 25 C.Specification Time points (days), 25 C. Test (Stability) T0 28 56 84 pH4.684 4.643 4.592 4.598 Osmolality 777 Assay 95.0%-110.0% 101.96% 99.59%98.91% 100.95% Epinephrine NMT 3.0% 0.30% 0.59% 0.59% 0.60% SulfonicAcid Adrenochrome NMT 0.5% 0.06% 0.13% 0.14% 0.15% Norepinephrine NMT4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND ND Total Impurities ≤12.0%0.47% 1.03% 1.48% 1.75% Chlorobutanol 1.42 mg/mL 1.36 mg/mL 1.25 mg/mL1.26 mg/mL Assay

TABLE 58 6 mg/mL or 6 mg/dose pH 4.7, 0.2% Chlorobutanol at 40 C.Specification Time points (days), 40 C. Test (Stability) T0 28 56 84 pH4.684 4.581 4.526 4.448 Osmolality 777 Assay 95.0%-110.0% 101.96% 99.11%98.43% 98.67% Epinephrine NMT 3.0% 0.30% 0.70% 0.70% 0.67% Sulfonic AcidAdrenochrome NMT 0.5% 0.06% 0.10% 0.10% 0.11% Norepinephrine NMT 4.0% NDND ND ND Adrenalone NMT 3.0% ND ND ND 0.06% Total Impurities ≤12.0%0.47% 1.97% 2.23% 3.14% Chlorobutanol 1.42 mg/mL 1.21 mg/mL 1.02 mg/mL1.01 mg/mL Assay

Example 16—Spray Characteristics

Administration of the epinephrine spray formulation using a nasaldelivery device was tested for spray characteristics including Dmax,ovality, D10, D50, D90, % volume <10 microns, and span. The results ofthe testing are shown in Table 59.

TABLE 59 Spray Characteristics Test Results Results Spray PatternEpinephine 2 mg bi-dose Epinephrine 5 mg (n = 5 at 30 mm) bi-dose FirstSpray Shape Ellipsoidal Ellipsoidal Density Relative uniform Relativeuniform density density Dmax 26.9 mm 24.0 mm Ovality 1.454 1.327 SecondSpray Shape Ellipsoidal Ellipsoidal Density Relative uniform Relativeuniform density density Dmax 26.2 mm 24.6 Ovality 1.378 1.377 DropletSize Distribution (n = 5 at 30 mm) First Spray D10 21.80 microns 19.79microns D50 53.69 microns 47.73 microns D90 126.3 microns 112.0 microns% Volume < 10 0.52% 0.75% microns Span 1.945 1.928 Second Spray D1020.58 microns 19.92 microns D50 50.51 microns 47.82 microns D90 119.0microns 112.0 microns % Volume < 10 0.57% 0.45% microns Span 1.941 1.925Particulates ≥10 microns: 98 ≥10 microns: 28 particles/containerparticles/container ≥25 microns: 1 ≥25 microns: 1 particle/containerparticle/container pH 4.6 4.7 Osmolality 425 693 (mOsm/kg)

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing thedisclosure. It is intended that the following claims define the scope ofthe disclosure and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

What is claimed is:
 1. A method of administering a pharmaceuticalsolution, comprising delivering a spray of the pharmaceutical solutionfrom a device into a nostril of a subject in need thereof in a mannerthat delivers the pharmaceutical solution in a round spray plume with anovality ratio less than about 1.4 when measured at a distance of fromabout 1 to about 10 cm from the device, wherein: (i) the device isadapted for nasal delivery; (ii) a volume of from about 20 μL to about250 μL of spray is delivered; and (iii) the pharmaceutical solutioncomprises from about 0.5 mg to about 100 mg of epinephrine, or apharmaceutically acceptable salt thereof, and the pharmaceuticalsolution further comprises from about 0.01% to about 0.1% (w/w) ofsodium bisulfite or sodium metabisulfite, and about 1% (w/w) diethyleneglycol monoethyl ether.
 2. The method of claim 1, wherein the sprayplume has a particle size distribution with a span of no more than about2.2 when measured at a distance of from about 1 to about 10 cm from thedevice.
 3. The method of claim 1, wherein the spray plume has a Dmax ofless than about 28 mm when measured at a distance of from about 1 toabout 10 cm from the device.
 4. The method of claim 1, wherein thedevice is a bi-dose device configured to deliver two sprays of thepharmaceutical solution.
 5. The method of claim 1, wherein the devicehas a single reservoir containing from about 125 μL to about 250 μL ofthe pharmaceutical solution.
 6. The method of claim 1, wherein thedevice comprises: (i) a vial comprising an opening; (ii) a cannula; and(iii) a rubber stopper; wherein the rubber stopper is configured toocclude the opening of the vial, and wherein the cannula is configuredto pierce the stopper when the plunger applies sufficient force to thecannula.
 7. The method of claim 1, wherein the device is a pre-primeddevice that is configured to be actuatable with one hand.
 8. The methodof claim 1, wherein a delivery time of the pharmaceutical solution isless than about 25 seconds.
 9. The method of claim 1, wherein thesubject is suffering from a severe allergic reaction from exposure orsuspected exposure to an allergen.
 10. The method of claim 9, whereinthe allergen is food, medication, or an insect bite or sting.
 11. Themethod of claim 9, wherein the subject exhibits one or more symptomschosen from: respiratory depression or distress, airway constriction,wheezing, tingling hands, feet, mouth, or scalp, shortness of breath,swelling or inflammation of the face, eyes, lips, tongue, or throat,hives, central nervous system depression, cardiovascular depression,altered level consciousness, mydriatic pupils, hypoxemia, hypotension,unresponsiveness to stimulus, unconsciousness, stopped breathing,erratic or stopped pulse, or vomiting.
 12. The method of claim 1,wherein the subject exhibits respiratory depression or distress, orcardiovascular depression.
 13. The method of claim 12, wherein thesubject is free from respiratory depression or distress for at leastabout 1 hour following the delivery of the pharmaceutical solution intothe nostril of the subject.
 14. A method of administering apharmaceutical solution, comprising delivering a spray of thepharmaceutical solution from a device into a nostril of a subject inneed thereof in a manner that delivers the pharmaceutical solution in aspray plume with a particle size distribution having a span of no morethan about 2.2 when measured at a distance of from about 1 to about 10cm from the device, wherein: the device is adapted for nasal delivery;(ii) a volume of from about 20 μL to about 250 μL of spray is delivered;and (iii) the pharmaceutical solution comprises from about 0.5 mg toabout 100 mg of epinephrine, or a pharmaceutically acceptable saltthereof, and the pharmaceutical solution further comprises from about0.01% to about 0.1% (w/w) of sodium bisulfite or sodium metabisulfite,and about 1% (w/w) diethylene glycol monoethyl ether.
 15. The method ofclaim 14, wherein the particle size distribution has a span of no morethan about 2.0 when measured at a distance of from about 1 to about 10cm from the device.
 16. The method of claim 14, wherein the device has asingle reservoir containing from about 125 μL to about 250 μL of thepharmaceutical solution.
 17. The method of claim 14, wherein the deviceis a bi-dose device configured to deliver two sprays of thepharmaceutical solution from a single reservoir.
 18. A method foradministering a pharmaceutical solution, comprising delivering a sprayof the pharmaceutical solution from a device into a nostril of a subjectin need thereof in a manner that delivers the pharmaceutical solution ina spray plume with a Dmax of less than about 28 mm when measured at adistance of from about 1 to about 10 cm from the device, wherein: (i)the device is adapted for nasal delivery; (ii) a volume of from about 20μL to about 250 μL of spray is delivered; and (iii) the pharmaceuticalsolution comprises from about 0.5 mg to about 100 mg of epinephrine, ora pharmaceutically acceptable salt thereof, and the pharmaceuticalsolution further comprises from about 0.01% to about 0.1% (w/w) ofsodium bisulfite or sodium metabisulfite, and about 1% (w/w) diethyleneglycol monoethyl ether.
 19. The method of claim 18, wherein the deviceis a bi-dose device configured to deliver two sprays of thepharmaceutical solution.
 20. The method of claim 18, wherein the Dmax isless than about 26 mm when measured at a distance of from about 1 toabout 10 cm from the device.